Comment Letters. Efficacy and Tolerability of the New Antiepileptic Drugs: Commentary on the Recently Published Practice Parameters

Transcription

1 Epilepsia, 45(12): , 2004 Blackwell Publishing, Inc. C 2004 International League Against Epilepsy Comment Letters Efficacy and Tolerability of the New Antiepileptic Drugs: Commentary on the Recently Published Practice Parameters We wish to make a commentary concerning the recent practice parameters issued by The Quality Standards and the Therapeutics and Technology Assessment Subcommittees of the American Academy of Neurology and the American Epilepsy Society (QSS & TTA) (1,2). These comprise a two-part assessment of evidence-based publications (up to March 2003) concerning new antiepileptic drugs (AEDs). Part 1 addresses their use in new onset epilepsy (1), and Part 2 in refractory epilepsy (2). We acknowledge the magnitude and difficulty of the task the QSS & TTA undertook in compiling their report. A particular issue with AED trials with which the subcommittees had to deal, is that diagnostic uncertainties and methodologic pressures confound analysis of studies, which are primarily designed to justify Food and Drug Administration (FDA) license requirements rather than address clinical practice needs (3). These issues compromise the conclusions of the QSS & TTA. Partly as a result, the recommendations as published may mislead physicians in the appropriate use of new AEDs and inadvertently perpetuate suboptimal practice in new clinical trials. In particular: 1. The QSS & TTA evidence-based assessment of AEDs does not accord with the evidence-based classification systems developed by the International League Against Epilepsy (4,5) and its relevant recommendations for AED trials that should be the basis for communication between physicians and for conducting clinical trials (6 8). A minimal requirement is to recognize the fundamental differences between partial (focal) and idiopathic generalized epilepsies (IGEs), because AEDs beneficial for partial epilepsies may be detrimental for IGEs (9,10). Indeed, even among IGEs, an AED beneficial in one type may be ineffective or may aggravate another type of the triad of IGE seizures (absences, myoclonic jerks, and generalized tonic clonic seizures; GTCSs) (9,10). The introduction of the term mixed seizure disorders as a class of epilepsy is misleading. Physicians might reasonably interpret this as referring to severe epilepsies such as Lennox Gastaut syndrome with multiple types of seizures. However, as used by the QSS & TTA, this term seems to refer to mixed and heterogeneous populations in AED trials with partial and generalized seizures, for which no data are specific to the individual groups. If this is so, the recommendations are hazardous because of indiscriminate inclusion of generalized (any type) and partial seizures. Evidence-based treatment is meaningless without accurate diagnosis of these disorders. 2. The term new-onset epilepsy as a therapeutic category discourages diagnostic precision and encourages inappropriate AED trial strategies such as, inclusion criteria do not specify seizure type or epilepsy syndrome so AED study results are generalized to the universe of patients with newly diagnosed epilepsy (11). In turn, this promotes detrimental indiscriminate use of carbamazepine (CBZ) and valproate (VPA) because neither of them is regarded as the single drug of choice for all patients with newly diagnosed epilepsy (11) despite established documentation that these are two different AEDs with different indications and contraindications in partial and generalized epilepsies. The term new onset itself is inaccurate. These are patients with newly identified unprovoked seizures ; three fourths (74%) experience multiple seizure episodes before their first medical contact (12). New-onset epilepsy encompasses all types of seizures and epilepsies irrespective of cause, prognosis, and response to AED. The purpose of such categorization should be to emphasize the need for meticulous diagnosis, which is possible for the majority of patients (13), and for specific management required on presentation. Efficacy and safety of AEDs are not determined by how long a diagnosis has been established. 3. The QSS & TTA report inappropriately validates some studies as class 1 and 2 despite violations of evidence-based clinical management. A recent class 1 study (11) was considered by the QSS & TTA as significant although one fourth (27%) of patients with IGE, including those with juvenile myoclonic epilepsy, were treated with CBZ, which was the comparator drug on the basis of the physicians intention to treat. Prescribing CBZ in juvenile myoclonic epilepsy and other IGEs is not recommended practice (9,10). Discontinuation of CBZ alone would probably benefit these patients. In another example, the QSS & TTA validates the 1646

2 LETTERS 1647 claim of a class 2 study that 64% patients became seizure free (14) although this was not clinically assessed and some seizure-free patients continued having absences on ambulatory EEGs (15). 4. The QSS & TTA does not consider the percentage of patients who became seizure free during the trials as a valid outcome measure, thus introducing bias in favor of less-effective AEDs. Seizurefree status is the ultimate, often achievable, goal of treatment. The argument that this figure does not represent the likelihood of patients remaining seizure free over a long-term period also applies to percentage seizure reduction, the measure assessed by the QSS & TTA. 5. The QSS & TTA report is sometimes imprecise and ambiguous. a. It confuses epilepsy classification with seizure classification (i.e.,...refractory GTCS. Definitive studies have not been performed with the other new AED in this epilepsy type. GTCSs are a type of seizure, not a type of epilepsy. b. GTCSs are erroneously equated in the report with any type of generalized seizures. This inaccuracy has adverse treatment implications because certain AEDs are contraindicated in some types of generalized seizures (absences and myoclonic jerks), irrespective of their effectiveness in GTCSs. c. Statements in the abstracts are inconsistent with the body of the document; for example, There is evidence that gabapentin... [has] efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders and repeated in Table 6 although gabapentin is not effective in mixed seizure disorders (1). d. Important and conclusive statements are contradicted within the report: In newly diagnosed epilepsy... topiramate is equivalent in efficacy and safety to 1,250 mg of fixed-dose valproic acid for idiopathic generalized seizures (1), conflicting with the findings of the report that At present, there is insufficient evidence to determine effectiveness in newly diagnosed primary or secondary generalized epilepsy for topiramate... (1). Furthermore, no such evidence exists regarding efficacy of this drug in typical absences and myoclonic jerks (which, like GTCSs, also are generalized seizures). 6. Although of immense importance in intent, the rating of the recommendations was assessed on established, probable or possible documentation of whether an AED is effective, ineffective, or harmful for the given condition in the specified population (1,2), the QSS & TTA does not provide any recommendations regarding a. established documentation of harmful effects of certain AEDs, such as that tiagabine (TGB) is a proabsence γ -aminobutyric acid (GABA)ergic agent used to induce, not to treat, absence seizures and absence status epilepticus. b. probable or possible documentation that in IGEs, gabapentin is ineffective, tiagabine is contraindicated, oxcarbazepine worsens absences and myoclonic jerks, whereas lamotrigine, levetiracetam, topiramate, and zonisamide may be effective agents. 7. The QSS & TTA report makes invalid presumptions rather than impartial evidence-based recommendations only. a. It suggests that the ineffectiveness of gabapentin in IGEs may be a dose effect: In retrospect, it is possible that the dose was too low. This argument could apply to any other new AED with poor efficacy, and not just to gabapentin. b. It makes presumptions regarding extension of the recommendations to children with epilepsies, promoting the possibility that once an AED has demonstrated efficacy as adjunctive therapy in refractory partial seizures in adults, the AED will demonstrate the same efficacy as adjunctive therapy in children older than 2 years. Children are particularly vulnerable to seizures, some common syndromes are specific to childhood only, response and adverse reactions to AEDs may be entirely different from that of the adults. Despite all these factors, controlled AED trials in children are sparse, an entirely unsatisfactory situation that should be emphasized in any relevant formal report. Practicing physicians, exercising their medical judgments, often use AEDs beyond their FDA indications and specified age/sex groups. Acceptance of the value of the patient therapeutic trial appears to be adopted by the QSS & TTA where recommendations are made for off-label uses. This is not a problem, provided that physicians are properly informed whether an AED is effective, ineffective, or harmful for the given condition in the specified population and obtain patients consent. Because these reports are likely to be influential in guiding prescribing practice beyond FDA approval limits, their review method

3 1648 LETTERS must be rigorous, and they must be rigorous in the correct use of terminology, interpretation of the method, and value of component clinical trials they review for the report. The committees responsible for making the recommendations should have adequate input from pediatric and adult clinical epileptologists on the importance of precise diagnosis. In conclusion, we believe that although the endeavor was laudable, we remain concerned that such authoritative recommendations, in their current form, fail to reinforce best clinical practice parameters. This letter also addresses a plea to influential Neurology and Epilepsy committees to consider issuing recommendations regarding the conduct of AED trials and resultant publications. These should insist on precise diagnostic definition of the populations studied and appropriate use of comparator AEDs so as to avoid confusion and inappropriate generalizations, as cited in this commentary. Chrysostomos P. Panayiotopoulos Department of Clinical Neurophysiology and Epilepsies St. Thomas Hospital Selim R. Benbadis Departments of Neurology & Neurosurgery Comprehensive Epilepsy Program University of South Florida and Tampa General Hospital Tampa, FL, U.S.A. Athanasios Covanis Aghia Sophia Children s Hospital Athens, Greece Olivier Dulac Universite Rene Descartes Paris, France John S. Duncan Department of Neurology Institute of Neurology University College London Orvar Eeg-Olofsson University Children s Hospital Uppsala, Sweden Colin D. Ferrie Leeds General Infirmary Leeds, United Kingdom Richard A. Grünewald Department of Neurology Royal Hallamshire Hospital Sheffield, United Kingdom Dorothee G. A. Kasteleijn-Nolst Trenite University Medical Centre Utrecht Utrecht, The Netherlands Michael Koutroumanidis Department of Clinical Neurophysiology and Epilepsies St. Thomas Hospital Zarko Martinovic Department of Epilepsy Institute of Mental Health Belgrade, Serbia and Montenegro Richard W. Newton Pediatric Neurology Royal Manchester Children s Hospital Manchester, United Kingdom Alasdair P. Parker Paediatric Epileptology Addenbrooke s Hospital Cambridge, United Kingdom Janvier Salas-Puig Department of Neurology Hospital Central Asturias Oviedo, Spain JWAS Sander Department of Clinical and Experimental Epilepsy Institute of Neurology University College London Simon Shorvon Institute of Neurology, University College London Kazuyoshi Watanabe Nagoya University Graduate School of Medicine Nagoya, Japan William P. Whitehouse Paediatric Neurology University of Nottingham Nottingham, United Kingdom

4 LETTERS 1649 Sotirios Youroukos Pediatric Neurology Athens University Medical School Aghia Sophia Children s Hospital Athens, Greece 1. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset Epilepsia 2004;45: French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, II: treatment of refractory Epilepsia 2004;45: Walker MC, Sander JW. Difficulties in extrapolating from clinical trial data to clinical practice: the case of antiepileptic drugs. Neurology 1997;49: Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22: Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30: Commission on Antiepileptic Drugs of the International League Against Epilepsy. Guidelines for clinical evaluation of antiepileptic drugs. Epilepsia 1989;30: Commission on antiepileptic drugs of the International League Against Epilepsy. Guidelines for antiepileptic drug trials in children. Epilepsia 1994;35: Benbadis SR, Luders HO. Epileptic syndromes: an underutilized concept [Editorial]. Epilepsia 1996;37: Genton P, Gelisse P, Thomas P, et al. Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy? Neurology 2000;55: Benbadis SR, Tatum WO, Gieron M. Idiopathic generalized epilepsy and choice of antiepileptic drugs. Neurology 2003;61: Privitera MD, Brodie MJ, Mattson RH, et al. Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy. Acta Neurol Scand 2003;107: Hauser WA, Rich SS, Annegers JF, et al. Seizure recurrence after a 1st unprovoked seizure: an extended follow-up. Neurology 1990;40: King MA, Newton MR, Jackson GD, et al. Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic imaging study of 300 consecutive patients. Lancet 1998;352: Frank LM, Enlow T, Holmes GL, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 1999;40: Panayiotopoulos CP. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 2000;41: Response: Efficacy and Tolerability of the New Antiepileptic Drugs We thank the authors for their careful review of our evidence-based assessment of new antiepileptic drugs (AEDs), published in Epilepsia and Neurology in 2004 (1 4). The authors have raised some concerns. We attempt to address our methods for this evidence-based report. 1. The authors have made several points regarding the nomenclature for the types of epilepsy that are addressed in our guideline. This is quite understandable, considering that classification is an extremely important aspect of epilepsy care. This is not, however, a guideline on diagnosis and classification. When assessing the evidence to make evidence-based conclusions, one can essentially only go where the money is. That is, one can address only the studies that have been performed in a controlled fashion, describe them completely, and reach conclusions. One cannot reperform the studies in the way that one might have designed them oneself. This is a frustrating aspect of evidence-based medicine, but not one that is novel to this particular assessment. It is certainly the duty of the committee writing the report to try to address methodology, where possible. More important, one must state the conclusions based on the evidence, not based on what one would like the evidence to be. We have made every effort to do this in our parameter, but understandably, this leads to some unusual nomenclature, mimicking the categorizations that were used in the research studies themselves. 2. A major concern of the authors is the inability to distinguish studies performed in idiopathic generalized epilepsy from those performed in partial epilepsy, or in newly diagnosed epilepsy. Of course, we realize that ideal method would consist of studies performed in a single epilepsy syndrome. Our method for this evidence-based review was to assess the data that were available to us. Very few studies have been performed that were powered to assess syndromes in isolation. Differences were not readily discernible within the studies themselves. For example, in the study by Brodie et al. (5), comparing carbamazepine (CBZ) with lamotrigine (LTG) in newly diagnosed epilepsy, no differences in outcome were found between patients with primary generalized, tonic clonic convulsions and patients with a focal onset. However, because of small numbers, we chose not to form any conclusions based on this. In our recommendations for future research, we very clearly make a plea for studies to be performed in specific syndromes. We agree that mixed seizure disorders is a term that could be misunderstood. We tried to clarify the meaning to the best of our ability. We also believe that physicians often find themselves in the circumstance of selecting an initial AED before a definitive syndromic diagnosis can be made. In the article by King et al. (6), cited by Panayiotopoulos, epilepsy syndrome was diagnosable in only 47% of

5 1650 LETTERS patients on clinical grounds, and in 77% with addition of the EEG, in the hands of experienced epileptologists, at first seizure presentation. Thus understanding the outcome in patients who are unclassified is a clinically important concept. 3. The authors make the curious claim that the term new-onset epilepsy is not of importance, and that efficacy and safety of AEDs are not determined by how long the diagnosis has been established. A great deal of recent investigation has regarded the prognosis in patients with newly diagnosed epilepsy versus those for whom AEDs already have failed. The studies seem to provide evidence that time since diagnosis may be as important as epilepsy syndrome in determining outcome of AED therapy (7). We had very little choice in selection of terms, because newly diagnosed versus refractory was the way patients were defined for the purposes of the studies that were performed. 4. The authors are concerned about a class I designation for a study that in their minds presents violations of evidence-based clinical management. The authors, many of whom are from outside the United States, and perhaps are not familiar with the classification scheme of the American Academy of Neurology, may not be aware that the issues that they discussed have no bearing on designation as class I, class II, etc. These classification schemes have the sole purpose of eliminating bias in studies. They do not address whether the study results are clinically valid. Because the particular study that they questioned was appropriately randomized and blinded, no question exists that the assignment of classification was correct. In this blinded study, patients were randomized to topiramate versus either valproate (VPA) or CBZ, based on the choice of the treating physician. The authors correctly point out that 27% of the patients randomized to treatment with CBZ had idiopathic generalized epilepsy. Randomization to treatment based on physician preference may be considered to be as valid a method as any other, because it may mimic real life. The guideline does not specifically say that topiramate (TPM) is effective in either partial or generalized epilepsy. 5. Another concern is that seizure freedom was not used as an outcome measure, and this might bias toward less effective drugs. As noted in the guideline, seizure freedom rarely is reported in the literature and therefore could not consistently be used. Even if this number is included, typically insufficient information is provided to determine whether this number is based on completers or includes dropouts. In several examples, high seizure-free outcomes have been reported, but subsequently it has been discovered that many of these seizure-free patients had dropped out within days of starting the study. 6. Again, the authors are concerned about imprecise and ambiguous classification. As noted earlier, the recommendations are based on the populations that were included in the trial, whether they represent a precise seizure classification or not. It is unclear where the authors concerns rest. They claim that [generalized tonic clonic seizures] GTCSs are equated with any type of generalized seizures. This is not the case. Under the category of generalized epilepsy, data are presented for any study that would be included in that category. The only study that was identified was one performed with TPM in GTCSs. It is very clearly stated both in the practice parameter and in the table that accompanies it, that the evidence specifically addresses refractory GTCSs. In addition, a discussion mentions that this may not be translatable to patients with similar syndromes, but not refractory disease. Another example relates to the abstract. The authors have extracted a portion of the sentence, which in its entirety reads, There is evidence either from comparative or dose-controlled trials that gabapentin (GBP), LTG, TPM, and oxcarbazepine (OXC) have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. This is consistent with the body of the document, because the statement in no way implies that each drug is effective in both partial and mixed seizure disorders. 7. The authors claim that the QSS and TTA do not provide any recommendations regarding established documentation of harmful effects of certain AEDs. They provide examples such as the proabsence effects of tiagabine (TGB) and OXC. Once again, these suggestions are based on common knowledge, rather than on controlled trial data. We had a great deal of difficulty handling adverse events in an evidence-based fashion. Of course, most adverse-event data of this type derives from case reports rather than randomized controlled trials. We did indicate that TGB was associated with spike wave stupor as an adverse event. Going beyond the statement would have been going beyond the available evidence. 8. The final, and perhaps most damning, claim is that the QSS and TTA reports make invalid presumptions rather than impartial evidence-based recommendations. We truly hope that this is not the case. Two examples are provided for this claim. The first is that, when talking about GBP for refractory GTCSs, we suggested that the ineffectiveness of GBP may be a dose effect. This is based on a statement that in retrospect, it is possible that the dose was too low. The dose used in this study was 1,200 mg GBP per day, which in refractory epilepsy would seem to be a low dose. However, this did not affect our recommendations whatsoever. The recommendation simply stated, There is insufficient evidence to recommend gabapentin for the treatment

6 LETTERS 1651 of refractory generalized tonic clonic seizures. The second example was directed at the statement indicating, The possibility that once an AED has demonstrated efficacy as adjunctive therapy in refractory partial seizures in adults, the AED will demonstrate the same efficacy as adjunctive therapy in children older than 2 years. The authors do not provide the sentence after this one, which read, However, trials in pediatric populations remain critically important to establish efficacy in this as well as other pediatric specific epilepsy syndromes. Again, the statement did not in any way affect the recommendations for use of drugs in children, which were completely impartial and evidence based. In summary, we fully support the authors conclusion that clinical trials should insist on precise definitions of populations studied. We cannot agree that our practice parameter was in any way misleading, incorrect, or biased. The authors would like to see recommendations that reinforce best clinical practice. Unfortunately, evidence-based guidelines are not based on best clinical practice. Rather they are based on the available evidence. Jacqueline A. French On Behalf of the Quality Standards Subcommittee of the American Academy of Neurology Department of Neurology, University of Pennsylvania 3West Gates, 3400 Spruce St., Philadelphia, PA French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Neurology 2004;62: French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Neurology 2004;62: French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory Epilepsia 2004;45: French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset Epilepsia 2004;45: Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy: UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet 1995;345: King MA, Newton MR, Jackson GD, et al. Epileptology of the firstseizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet 1998;352: Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001;42: Hyperventilation and Epileptic Seizures The article by Holmes et al. (1) on hyperventilation (HV) and seizures concludes that their findings provide compelling evidence that both localization-related and generalized epilepsies are relatively resistant to routine HV activation in adults and adolescents. I disagree with their interpretation. Absence of a witnessed clinical or electrographic seizure, especially with a retrospective study, does not imply that epilepsies are resistant to HV. We often use HV when attempting ictal single-photon emission computed tomography (SPECT) scan in our hospitalized telemetry patients and have been doing so for the last several years. Of the last 40 to 50 patients who underwent HV, seizures were personally witnessed in three to four patients (unpublished data). These were all adult patients with localization-related epilepsies. Seizures can occur during HV or a few minutes after the procedure. This is significantly contradictory to the numbers provided by the author. While conducting routine EEGs, the technologists encourage a good effort with HV but may not consistently get ideal results. Second, HV by technologists is not aimed at provoking a seizure but rather at unmasking epileptiform activity. Therefore a trained technologist will often stop HV if a suspicion exists that the patient is about to seize. Based on the observation of Holmes et al., it would be more appropriate to conclude that seizures are very infrequently witnessed during routine HV. However, this does not provide compelling evidence that epilepsies are relatively resistant to this procedure. S. Nizam Ahmed University of Alberta, Medicine Edmonton, Alberta, Canada 1. Holmes MD, Dewaraja AS, Vanhatalo S. Does hyperventilation elicit epileptic seizures? Epilepsia 2004;45: Response: Hyperventilation and Epileptic Seizures This letter is in response to the comments by Dr. Ahmed concerning our recent report on the effectiveness of voluntary hyperventilation (HV) in eliciting seizures in patients with proven epilepsy (1). Dr. Ahmed takes issue with our conclusion that seizures in adults with either generalized and localization-related epilepsy syndromes are relatively resistant to routine HV activation. This is a surprising position, given the fact that in >400 consecutive

7 1652 LETTERS and unselected patients with proven epilepsy in our series, HV elicited a clinical seizure in only two (i.e., fewer than one half of 1% of the total number). Given these results, we find it difficult to conceive that an objective observer would reach any conclusion other than the one we reached in our study. As a counterargument, Dr. Ahmed offers his anecdotal experience with HV in eliciting seizures while obtaining ictal single-photon emission computed tomography (SPECT) studies. Unfortunately, the data that Dr. Ahmed presents are imprecise and unpublished. Therefore it is impossible to comment further on his findings. Dr. Ahmed is incorrect in his assertion that routine HV by technologists performing standard EEG is not aimed at provoking a seizure. On the contrary, the point of HV is to attempt to elicit, if not epileptic seizures, at least interictal epileptiform discharges. That is the reason HV for decades has been used in clinical EEG laboratories around the world; it is based on the widespread, but erroneous, belief that HV is an effective provocative maneuver. With the caveat that our results may not apply to children (as we noted in our report), HV performed during routine EEG recordings will rarely be associated with clinical seizures, even in individuals with unequivocal epilepsy. Mark D. Holmes Regional Epilepsy Center University of Washington Seattle, Washington 1. Holmes M, Dewaraja A, Vanhatalo S. Does hyperventilation elicit epileptic seizures? Epilepsia 2004;45: