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Self reported adverse effects of mono and polytherapy for epilepsy
Seizure 21 (2012) 610–613
Contents lists available at SciVerse ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Self reported adverse effects of mono and polytherapy for epilepsy Tom Andrew, Kristijonas Milinis, Gus Baker, Udo Wieshmann * The Walton Centre for Neurology & Neurosurgery and University of Liverpool, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 March 2012 Received in revised form 24 June 2012 Accepted 26 June 2012
Purpose: Adverse effects of anti epileptic drugs (AEDs) can significantly affect the life of people with epilepsy. We used a register to determine if polytherapy with AED has more adverse effects than monotherapy. Methods: We established a register for people with epilepsy (www.UKAED.info). Participants were requested to complete the Liverpool Adverse Event Profile (LAEP) to quantify adverse effects. We also recorded type of epilepsy, seizure control and AED including drug doses. Five hundred and seventy six complete data sets were available, monotherapy (n = 186), polytherapy (n = 325) and control subjects not taking AED (n = 65). Results: The mean LAEP scores in polytherapy (45.56, confidence interval (CI) = 44.36–46.76) were significantly higher than the mean LAEP scores in monotherapy (42.29, CI = 40.65–44.02) and the mean LAEP scores in controls (33.25, CI = 31.05–35.44). Tiredness, memory problems and difficulty concentrating were the most common symptoms in patients taking AED and were consistently higher in polytherapy than in monotherapy. Tiredness was reported as always or sometimes being a problem in (polytherapy/monotherapy/controls) 82.5%/75.6%/64.6%, memory problems in 76%/63.2%/29.2% and difficulty concentrating in 68%/63.9%/30.8%. The proportion of seizure-free patients was significantly lower in the polytherapy group (17%) than in the monotherapy group (55%). Depression rates between the monotherapy and polytherapy groups were similar. Drug dosages were higher in polytherapy, however this did not reach statistical significance. Conclusion: Patients on polytherapy had significantly higher LAEP scores than patients on monotherapy. This should be carefully discussed with the patient before a second AED is added. ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Adverse effects Aepileptic drugs Epilepsy
1. Introduction Epilepsy is one of the most common chronic neurological diseases, usually requiring long term treatment with anti epileptic drugs (AEDs). Epileptic seizures, additional co-morbidity and adverse effects (AE) of AED can all greatly affect the quality of life of those suffering from epilepsy.1 There are currently 25 licensed AED on the market in the UK, which offer numerous combination therapies. This provides a great challenge for the clinician when deciding on a suitable treatment plan. Monotherapy is commonly viewed as the ‘gold standard’ of pharmacological treatment. However, with the introduction of so many new generation AED with an ‘‘add on’’ license, polytherapy has became a reality for
Abbreviations: AED, anti epileptic drug; AE, adverse effect; CBZ, Carbamazepine; LTG, Lamotrigine; LEV, Levetiracetam; PHT, Phenytoin; VPA, Valproate; LAEP, Liverpool Adverse Event Profile; CLE, cryptogenic localisation related epilepsy; SLE, symptomatic localisation related epilepsy; GE, generalised epilepsy; CI, confidence interval; SD, standard deviation. * Corresponding author at: The Walton Centre for Neurology & Neurosurgery, Lower Lane, Liverpool, UK. Tel.: +44 0151 529 5687; fax: +44 0151 529 5513. E-mail address: [email protected] (U. Wieshmann).
many patients.2 A recent study from Norway showed that 18% of patients were on polytherapy. The most common combinations were Lamotrigine with Valproate and Levetiracetam with Carbamazepine.3 A number of studies compared the efficacy and severity of AE between polytherapy and monotherapy, however a general consensus has not been achieved. Shorvon and Reynolds emphasised three major problems associated with polypharmacotherapy: chronic toxicity, exacerbation of seizures and drug interactions, therefore they strongly supported the use of high dose monotherapy before employing add-on therapy.4 However, the study had been carried out before the introduction of the newer AED, which potentially could be safely employed in polytherapy. Currently, little is known about the prevalence of AE including cognitive and psychological disturbances caused by AED but the prevalence is likely to be high.5 A study suggested that doctors may under-report severe AE6 and doctors may miss or fail to report milder symptoms even more frequently. Recording symptoms directly from the patient may have advantages to assess AE and to monitor AED in clinical practice. Our aim was to utilise the UKAED Register, a self-referral register to compare the AE profile of AED. The register is based on the Liverpool Adverse Event Profile (LAEP)
1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2012.06.013
T. Andrew et al. / Seizure 21 (2012) 610–613
611
Sulthiame, Pyridoxine. The total LAEP and individual symptom scores were calculated and compared employing several statistical tools including ANOVA, Bonferroni’s, Tukey’s and chi squared tests on SPSS software. We also calculated the LAEP score of the individual drugs (CBZ, VPA, LTG, LEV) as well as the four most common drug combinations (CBZ with LEV, VPA with LEV, CBZ with LTG, PHT with LEV). Furthermore, possible confounding factors including depression and seizure control were assessed.11 Depression scores were compared amongst the groups along with the drug dosages. The proportion of seizure-free patients was calculated in monotherapy and polytherapy groups. 3. Results
Fig. 1. Box plot showing Liverpool Adverse Event Profile scores for controls, patients on monotherapy and patients on polytherapy. The dark line within the box represents the median, the end of the box fall at the upper and lower quartiles. The whiskers were drawn from the lower and upper quartile to the data point, which was still within 1.5 of the inter-quartile range.
questionnaire. The LAEP is a validated tool which assesses the physical, psychological and cognitive state (Fig. 1).7–11 2. Methods The UKAED Register is a prospective register to study the efficacy and side effects of AED. The register was established at The Walton Centre for Neurology & Neurosurgery, Liverpool in July 2008. Anybody who takes AED can self-refer to the register. The register is independent from the pharmaceutical industry and has ethical approval. For the current analysis we included all subjects with complete data sets. Subjects were divided in three groups: monotherapy (patients on 1 AED), polytherapy (patients > 1 AED) and control subjects. The control subjects were either employees at The Walton Centre, students at Liverpool University or patients with single seizures or very infrequent seizures not taking AED. All the data was collected using the Liverpool Adverse Event Profile (LAEP) questionnaire, which was completed by the patients either electronically via http://www.ukaed/info or in paper form in the Mersey Regional Epilepsy clinic at The Walton Centre in Liverpool. The variables recorded in LAEP included 19 self-reported symptoms. These are rated by the patient/carer on the 4-point Likert scale. 1 indicates the symptom is never a problem; 2, it is rarely a problem; 3, it is sometimes a problem; and 4, always or often a problem. Hence it is possible to analyse the scores of individual symptoms as well as calculate overall symptom score.7– 9 The following features of the respondents were also recorded in the questionnaire: gender, age, sex, seizure control, AED and their dosages, epileptic syndrome and other co-morbidities. The data was collected between July 2008 and August 2011. Initial number of subjects was 601. After excluding patients based on insufficient amount of data and unanswered items of the questionnaire, the final number of subjects was 576: 65 controls, 186 monotherapy and 325 polytherapy. Our patients were on a wide range of AED including: Carbamazepine (CBZ), Valproate (VPA), Lamotrogine (LTG), Phenytoin (PHT), Oxcarbazepine, Levetiracetam (LEV), Clobazam (CLO), Topiramate (TPM), Primidone, Zonizamide (ZNS), Gabapentin, Lacosomide, Clonazepam, Azetazolamide, Rufinamide, Pregabalin, Eslicarbazepine, Phenobarbitone, Vigabatrin, Diazepam, Nitrazepam, Lorazepam, Piracetam, Ethosuximide,
The mean LAEP score was lowest in the control group (33.25, confidence interval (CI) 31.05–35.44). Significantly higher mean LAEP scores were observed in monotherapy 42.29 (CI 40.65–44.02) and polytherapy 45.56 (CI 44.36–46.76). An ANOVA with Bonferroni’s and Tukey’s tests showed significant differences between the three groups (p-value < 0.001). For patients on monotherapy, we compared the most commonly used drugs CBZ, VPA, LEV and LTG. CBZ had the highest LAEP score (n = 46, mean LAEP score 44.83, CI 41.68–47.97), followed by LEV (n = 37 mean LAEP score 41.68, CI 37.95–45.40), LTG (n = 42, mean LAEP score 40.05, CI 36.36–43.73) and VPA (n = 32, mean LAEP score 40.03, CI 35.29–44.80) but the differences did not reach statistical significance. Similar trends were observed in patients on polytherapy with two AED. The lowest mean LAEP score was in patients on a combination of LTG with CBZ (n = 5, mean LAEP score 40.00, CI 26.42–53.57). Higher scores were seen in combinations of CBZ with LEV (n = 24, mean LAEP score 44.08, CI 39.83–48.32), LEV with VPA (n = 13, mean LAEP score 44.38, CI 36.45–52.31), and LEV with PHT (n = 8, mean LAEP score 44.50, CI 40.77–46.87). LEV was the most commonly prescribed drug in combination therapy (n = 45). Control subjects had the lowest mean LAEP score and consistently scored lower in each individual subscore. Polytherapy patients had higher LAEP subscores than monotherapy patients, except for disturbed sleep and dizziness. The most common symptoms were tiredness, memory problems and difficulty concentrating in both monotherapy and polytherapy. The frequencies in polytherapy/monotherapy/controls for tiredness being always or sometimes occurring were 82.5%/ 75.6%/64.6%, for memory problems always or sometimes occurring 76%/63.2%/29.2% and for difficulty concentrating always or sometimes occurring 68%/63.9%/30.8%. There was no significant difference in the proportion of patients with depression reported as always or sometimes being a problem between monotherapy (42.3%) and polytherapy (48.1%). We regarded the presence of depression if LAEP score was more than 2 (3 – sometimes a problem, 4 – always a problem). There was a significantly higher proportion of seizure-free patients in the monotherapy group (54.3%) than polytherapy (16.6%). The mean daily AED dose for CBZ, LTG, OXC, LEV, VPA were higher in polytherapy than in monotherapy. The mean daily dose of PHT was lower in polytherapy than in monotherapy. However, confidence intervals overlapped in all 6 AEDs. 4. Discussion Our paper reflects modern day practice. Newer AED including Keppra are used ever more readily. Using validated measures to assess patient outcomes, we found statistically significantly higher rates of self-reported symptoms in the polytherapy group (mean LAEP score 45.56, CI 44.36–46.76) compared to monotherapy group (mean LAEP score 42.29, CI 40.65–44.02). Overall, adverse
T. Andrew et al. / Seizure 21 (2012) 610–613
612 Table 1 Clinical data and LAEP results.
n Sex (f/m) Age [years] (SD) CLE/SLE/GE/other CBZ/LTG/LEV/VPA/other Number of co-morbidities Seizure-free rate [%]a LAEP scores (95%CI)a Depression [%]b Tiredness [%]b Memory problems [%]b Difficulty concentrating [%]b
Control
Monotherapy
Polytherapy
65 37/28 31.35 (11.52) n/a n/a 2 n/a 33.25 (31.05–35.44) n/a 64.6 29.2 30.8
186 120/66 39.47 (13.71) 76/35/67/8 46/42/37/32/31 64 54.3 42.29 (40.5–44.02) 42.3 75.6 63.2 63.9
325 183/142 42.93 (14.06) 104/84/122/15 117/118/156/72/(n/a) 163 16.3 45.56 (44.36–46.76) 48.1 82.5 76.0 68
CLE/SLE/GE = cryptogenic localisation related epilepsy/symptomatic localisation related epilepsy/generalised epilepsy, CI = confidence interval. a The differences between mono and polytherapy were statistically significant. b Symptoms were reported as always or sometimes being a problem.
effects of AEDs were very common in our study, which further supports pre-existing evidence.4,12,13 Our observation that polytherapy causes more side effects than monotherapy was consistent with the results of Namazi et al.14 and Haag et al.1 In addition, Thomas et al.12 showed that polytherapy was associated with lower quality of life while Haag et al.1 implicated worse employment opportunities in patients on multiple AEDs. In contrast, a single randomised controlled trial (RCT) failed to show any significant difference,15 however, patients were only on one or two old drugs (CBZ versus CBZ and VPA), whereas in our study patients were on numerous combinations typically including at least one new AED (Table 1). It is also worth noting that in our study the LAEP scores in the polytherapy group were often above 45, which is considered intoxication according to Gilliam et al.7 The mean LAEP was >45 in the polytherapy group. The three most common symptoms reported in our study were all central nervous system (CNS) related and included: tiredness, memory problems and difficulty concentrating. The frequencies of reported AE were very high in both polytherapy and monotherapy, although higher in polytherapy. More than 80% in the polytherapy group and more that three quarters in the monotherapy group complained about tiredness, more than three quarters in the polytherapy group and almost two thirds of patients complained about memory problems and about two thirds in both groups complained about difficulties concentrating as always or at least sometimes being a problem. Our data is in keeping with the results of Carpay et al.,5 who reported almost 60% of patients had CNS related AE. Depression and uncontrolled epilepsy were identified as confounding factors.11,13 A higher prevalence of depression in patients on AED than in control subjects may explain the higher LAEP scores in patients on AED compared to controls but is unlikely to explain the higher LAEP scores in polytherapy compared to monotherapy because the depression rates were very similar in poly and monotherapy (48.7% and 42.3%, respectively). Uncontrolled epilepsy in the polytherapy group may have affected the result. Nevertheless, our data highlights the burden of AED. Doctors should resist the temptation to over-treat patients. However, any symptom should not automatically be regarded as an AE of AED in patients with depression and uncontrolled epilepsy. Patients should be encouraged to take AED regularly as non-adherence may be associated with an increased mortality unless it is certain that symptoms are caused by the AED.16 In addition to our main comparison of poly and monotherapy we performed a subgroup analysis looking for differences in different AED. The result should be interpreted with caution but showed interesting trends. In our study CBZ (n = 46, mean LAEP score 44.83, CI 41.68–47.97) was the least well tolerated
monotherapy AED but the confidence intervals overlapped with other AED used in monotherapy. The LAEP score of CBZ in combination with LEV (n = 24, mean = 44.08, CI = 39.83–48.32) was not higher than in CBZ monotherapy. Interestingly CBZ with LTG had a lower mean LAEP (n = 5, mean = 40.00, CI = 26.42–53.57) than CBZ in monotherapy but the numbers were too small to draw any firm conclusions. We showed a trend for LTG having less AE but this did not reach significance, potentially because of the small numbers. According to the SANAD trial LTG is better than CBZ largely because of the better AE profile of LTG.17 Brodie et al. also reported that LTG is better tolerated than CBZ.18 Our approach to use a self-referral register to assess possible AE of AED has a number of limitations. Recorded symptoms are reported by patients and have to be taken on trust. The data in the register may be biased towards more severe cases. Controls were not matched to cases and the mean age in controls was lower than in patients on AED. Polytherapy patients had more severe epilepsy than monotherapy in our study, frequent seizures were likely to be a confounding factor. In addition, there was a trend for higher AED doses in polytherapy than in monotherapy. There are numerous possible combinations for polytherapy. In the current analysis the numbers for each combination were too small to be certain that there are differences between the polytherapies. We hope that with increasing numbers of patients we will be able to provide more robust data on individual combination therapies. The register cannot replace a RCT. Having said this, we think that a register adds to the body of evidence of the burden on AED. We think that the information from the register was valuable and perhaps even more applicable because the AED used reflected current clinical practice. In summary, polytherapy had significantly higher LAEP scores than monotherapy. This should be discussed with the patient before a second AED is added. Conflict of interest statement None of the authors have any conflicts of interest to disclose. Acknowledgements The UKAED Register has been kindly supported with a grant from Epilepsy Action. We would like to thank Carol Chadwick for proof reading the paper. References 1. Haag A, Strzelcyk A, Bauer S, Kuhnem S, Hamer HM, Rosenow F. Quality of life and employment status are correlated with antiepileptic monotherapy versus polytherapy and not with use of ‘‘newer’’ versus ‘‘classic’’ drugs: results of the ‘‘Compliant 2006’’ survey in 907 patients. Epilepsy & Behavior 2010:618–22.
T. Andrew et al. / Seizure 21 (2012) 610–613 2. Kwan P, Brodie MJ. Drug treatment of epilepsy: when does it fail and how to optimize its use? CNS Spectrums 2004;9:110–9. 3. Landmark CJ, Fossmark H, Larsson PG, Rytter E, Johannessen SI. Prescription patterns of antiepileptic drugs in patients with epilepsy in a nation-wide population. Epilepsy Research 2011;95:51–9. 4. Shorvon SD, Reynolds EH. Unnecessary polypharmacy for epilepsy. British Medical Journal 1977;1:1635–7. 5. Carpay JA, Aldenkamp AP, van Donselaar CA. Complaints associated with the use of antiepileptic drugs: results from a community-based study. Seizure 2005;14:198–206. 6. Barrow P, Waller P, Wise L. Comparison of hospital episodes with ‘druginduced’ disorders and spontaneously reported adverse drug reactions. British Journal of Clinical Pharmacology 2005;61:233–7. 7. Gilliam FG, Fessler AJ, Baker G, Vahle V, Carter J, Attarian H. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology 2004;62:23–7. 8. Baker GA, Jacoby A, Buck D, Stalgis C, Monnet D. Quality of life of people with epilepsy: a European study. Epilepsia 1997;38:353–62. 9. Jacoby A, Gamble C, Doughty J, Marson A, Chadwick D. Quality of life outcomes of immediate or delayed treatment of early epilepsy and single seizures. Neurology 2007;68:1188–96. 10. Wieshmann UC, Tan GM, Baker G. Self-reported symptoms in patients on antiepileptic drugs in monotherapy. Acta Neurologica Scandinavica 2011; 124:355–8.
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11. Panelli RJ, Kilpatrick C, Moore SM, Matkovic Z, D’Souza WJ, O’Brien T. The Liverpool Adverse Events Profile: relation to AED use and mood. Epilepsia 2007;48:456–63. 12. Thomas SV, Koshy S, Sudhakaran NCR, Sarma SP. Frequent seizures and polytherapy can impair quality of life in persons with epilepsy. Neurology India 2005;53:46–50. 13. Salas-Puig J, Gil-Nagel A, Serratosa JM, Sanchez-Alvarez JC, Elices E, Villanueva V, et al. Self-reported memory problems in everyday activities in patients with epilepsy treated with antiepileptic drugs. Epilepsy & Behavior 2009:622–7. 14. Namazi S, Borhani-Haghighi A, Karimzadeh I. Adverse reactions to antiepileptic drugs in epileptic outpatients: a cross-sectional study in Iran. Clinical Neuropharmacology 2011;34:79–83. 15. Deckers CLP, Hekster YA, Keyser A, Lier HJJ, Meinardi H, Renier WO. Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia 2001;42:1387–94. 16. Faught E, Duh MS, Weiner JR, Guerin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM study. Neurology 2008;71:1572–8. 17. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. 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(9566):1000–15. 18. Brodie MJ, Overstall PW, Giorgi L. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Research 1999:81–7.
Contents lists available at SciVerse ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Self reported adverse effects of mono and polytherapy for epilepsy Tom Andrew, Kristijonas Milinis, Gus Baker, Udo Wieshmann * The Walton Centre for Neurology & Neurosurgery and University of Liverpool, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 March 2012 Received in revised form 24 June 2012 Accepted 26 June 2012
Purpose: Adverse effects of anti epileptic drugs (AEDs) can significantly affect the life of people with epilepsy. We used a register to determine if polytherapy with AED has more adverse effects than monotherapy. Methods: We established a register for people with epilepsy (www.UKAED.info). Participants were requested to complete the Liverpool Adverse Event Profile (LAEP) to quantify adverse effects. We also recorded type of epilepsy, seizure control and AED including drug doses. Five hundred and seventy six complete data sets were available, monotherapy (n = 186), polytherapy (n = 325) and control subjects not taking AED (n = 65). Results: The mean LAEP scores in polytherapy (45.56, confidence interval (CI) = 44.36–46.76) were significantly higher than the mean LAEP scores in monotherapy (42.29, CI = 40.65–44.02) and the mean LAEP scores in controls (33.25, CI = 31.05–35.44). Tiredness, memory problems and difficulty concentrating were the most common symptoms in patients taking AED and were consistently higher in polytherapy than in monotherapy. Tiredness was reported as always or sometimes being a problem in (polytherapy/monotherapy/controls) 82.5%/75.6%/64.6%, memory problems in 76%/63.2%/29.2% and difficulty concentrating in 68%/63.9%/30.8%. The proportion of seizure-free patients was significantly lower in the polytherapy group (17%) than in the monotherapy group (55%). Depression rates between the monotherapy and polytherapy groups were similar. Drug dosages were higher in polytherapy, however this did not reach statistical significance. Conclusion: Patients on polytherapy had significantly higher LAEP scores than patients on monotherapy. This should be carefully discussed with the patient before a second AED is added. ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Adverse effects Aepileptic drugs Epilepsy
1. Introduction Epilepsy is one of the most common chronic neurological diseases, usually requiring long term treatment with anti epileptic drugs (AEDs). Epileptic seizures, additional co-morbidity and adverse effects (AE) of AED can all greatly affect the quality of life of those suffering from epilepsy.1 There are currently 25 licensed AED on the market in the UK, which offer numerous combination therapies. This provides a great challenge for the clinician when deciding on a suitable treatment plan. Monotherapy is commonly viewed as the ‘gold standard’ of pharmacological treatment. However, with the introduction of so many new generation AED with an ‘‘add on’’ license, polytherapy has became a reality for
Abbreviations: AED, anti epileptic drug; AE, adverse effect; CBZ, Carbamazepine; LTG, Lamotrigine; LEV, Levetiracetam; PHT, Phenytoin; VPA, Valproate; LAEP, Liverpool Adverse Event Profile; CLE, cryptogenic localisation related epilepsy; SLE, symptomatic localisation related epilepsy; GE, generalised epilepsy; CI, confidence interval; SD, standard deviation. * Corresponding author at: The Walton Centre for Neurology & Neurosurgery, Lower Lane, Liverpool, UK. Tel.: +44 0151 529 5687; fax: +44 0151 529 5513. E-mail address: [email protected] (U. Wieshmann).
many patients.2 A recent study from Norway showed that 18% of patients were on polytherapy. The most common combinations were Lamotrigine with Valproate and Levetiracetam with Carbamazepine.3 A number of studies compared the efficacy and severity of AE between polytherapy and monotherapy, however a general consensus has not been achieved. Shorvon and Reynolds emphasised three major problems associated with polypharmacotherapy: chronic toxicity, exacerbation of seizures and drug interactions, therefore they strongly supported the use of high dose monotherapy before employing add-on therapy.4 However, the study had been carried out before the introduction of the newer AED, which potentially could be safely employed in polytherapy. Currently, little is known about the prevalence of AE including cognitive and psychological disturbances caused by AED but the prevalence is likely to be high.5 A study suggested that doctors may under-report severe AE6 and doctors may miss or fail to report milder symptoms even more frequently. Recording symptoms directly from the patient may have advantages to assess AE and to monitor AED in clinical practice. Our aim was to utilise the UKAED Register, a self-referral register to compare the AE profile of AED. The register is based on the Liverpool Adverse Event Profile (LAEP)
1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2012.06.013
T. Andrew et al. / Seizure 21 (2012) 610–613
611
Sulthiame, Pyridoxine. The total LAEP and individual symptom scores were calculated and compared employing several statistical tools including ANOVA, Bonferroni’s, Tukey’s and chi squared tests on SPSS software. We also calculated the LAEP score of the individual drugs (CBZ, VPA, LTG, LEV) as well as the four most common drug combinations (CBZ with LEV, VPA with LEV, CBZ with LTG, PHT with LEV). Furthermore, possible confounding factors including depression and seizure control were assessed.11 Depression scores were compared amongst the groups along with the drug dosages. The proportion of seizure-free patients was calculated in monotherapy and polytherapy groups. 3. Results
Fig. 1. Box plot showing Liverpool Adverse Event Profile scores for controls, patients on monotherapy and patients on polytherapy. The dark line within the box represents the median, the end of the box fall at the upper and lower quartiles. The whiskers were drawn from the lower and upper quartile to the data point, which was still within 1.5 of the inter-quartile range.
questionnaire. The LAEP is a validated tool which assesses the physical, psychological and cognitive state (Fig. 1).7–11 2. Methods The UKAED Register is a prospective register to study the efficacy and side effects of AED. The register was established at The Walton Centre for Neurology & Neurosurgery, Liverpool in July 2008. Anybody who takes AED can self-refer to the register. The register is independent from the pharmaceutical industry and has ethical approval. For the current analysis we included all subjects with complete data sets. Subjects were divided in three groups: monotherapy (patients on 1 AED), polytherapy (patients > 1 AED) and control subjects. The control subjects were either employees at The Walton Centre, students at Liverpool University or patients with single seizures or very infrequent seizures not taking AED. All the data was collected using the Liverpool Adverse Event Profile (LAEP) questionnaire, which was completed by the patients either electronically via http://www.ukaed/info or in paper form in the Mersey Regional Epilepsy clinic at The Walton Centre in Liverpool. The variables recorded in LAEP included 19 self-reported symptoms. These are rated by the patient/carer on the 4-point Likert scale. 1 indicates the symptom is never a problem; 2, it is rarely a problem; 3, it is sometimes a problem; and 4, always or often a problem. Hence it is possible to analyse the scores of individual symptoms as well as calculate overall symptom score.7– 9 The following features of the respondents were also recorded in the questionnaire: gender, age, sex, seizure control, AED and their dosages, epileptic syndrome and other co-morbidities. The data was collected between July 2008 and August 2011. Initial number of subjects was 601. After excluding patients based on insufficient amount of data and unanswered items of the questionnaire, the final number of subjects was 576: 65 controls, 186 monotherapy and 325 polytherapy. Our patients were on a wide range of AED including: Carbamazepine (CBZ), Valproate (VPA), Lamotrogine (LTG), Phenytoin (PHT), Oxcarbazepine, Levetiracetam (LEV), Clobazam (CLO), Topiramate (TPM), Primidone, Zonizamide (ZNS), Gabapentin, Lacosomide, Clonazepam, Azetazolamide, Rufinamide, Pregabalin, Eslicarbazepine, Phenobarbitone, Vigabatrin, Diazepam, Nitrazepam, Lorazepam, Piracetam, Ethosuximide,
The mean LAEP score was lowest in the control group (33.25, confidence interval (CI) 31.05–35.44). Significantly higher mean LAEP scores were observed in monotherapy 42.29 (CI 40.65–44.02) and polytherapy 45.56 (CI 44.36–46.76). An ANOVA with Bonferroni’s and Tukey’s tests showed significant differences between the three groups (p-value < 0.001). For patients on monotherapy, we compared the most commonly used drugs CBZ, VPA, LEV and LTG. CBZ had the highest LAEP score (n = 46, mean LAEP score 44.83, CI 41.68–47.97), followed by LEV (n = 37 mean LAEP score 41.68, CI 37.95–45.40), LTG (n = 42, mean LAEP score 40.05, CI 36.36–43.73) and VPA (n = 32, mean LAEP score 40.03, CI 35.29–44.80) but the differences did not reach statistical significance. Similar trends were observed in patients on polytherapy with two AED. The lowest mean LAEP score was in patients on a combination of LTG with CBZ (n = 5, mean LAEP score 40.00, CI 26.42–53.57). Higher scores were seen in combinations of CBZ with LEV (n = 24, mean LAEP score 44.08, CI 39.83–48.32), LEV with VPA (n = 13, mean LAEP score 44.38, CI 36.45–52.31), and LEV with PHT (n = 8, mean LAEP score 44.50, CI 40.77–46.87). LEV was the most commonly prescribed drug in combination therapy (n = 45). Control subjects had the lowest mean LAEP score and consistently scored lower in each individual subscore. Polytherapy patients had higher LAEP subscores than monotherapy patients, except for disturbed sleep and dizziness. The most common symptoms were tiredness, memory problems and difficulty concentrating in both monotherapy and polytherapy. The frequencies in polytherapy/monotherapy/controls for tiredness being always or sometimes occurring were 82.5%/ 75.6%/64.6%, for memory problems always or sometimes occurring 76%/63.2%/29.2% and for difficulty concentrating always or sometimes occurring 68%/63.9%/30.8%. There was no significant difference in the proportion of patients with depression reported as always or sometimes being a problem between monotherapy (42.3%) and polytherapy (48.1%). We regarded the presence of depression if LAEP score was more than 2 (3 – sometimes a problem, 4 – always a problem). There was a significantly higher proportion of seizure-free patients in the monotherapy group (54.3%) than polytherapy (16.6%). The mean daily AED dose for CBZ, LTG, OXC, LEV, VPA were higher in polytherapy than in monotherapy. The mean daily dose of PHT was lower in polytherapy than in monotherapy. However, confidence intervals overlapped in all 6 AEDs. 4. Discussion Our paper reflects modern day practice. Newer AED including Keppra are used ever more readily. Using validated measures to assess patient outcomes, we found statistically significantly higher rates of self-reported symptoms in the polytherapy group (mean LAEP score 45.56, CI 44.36–46.76) compared to monotherapy group (mean LAEP score 42.29, CI 40.65–44.02). Overall, adverse
T. Andrew et al. / Seizure 21 (2012) 610–613
612 Table 1 Clinical data and LAEP results.
n Sex (f/m) Age [years] (SD) CLE/SLE/GE/other CBZ/LTG/LEV/VPA/other Number of co-morbidities Seizure-free rate [%]a LAEP scores (95%CI)a Depression [%]b Tiredness [%]b Memory problems [%]b Difficulty concentrating [%]b
Control
Monotherapy
Polytherapy
65 37/28 31.35 (11.52) n/a n/a 2 n/a 33.25 (31.05–35.44) n/a 64.6 29.2 30.8
186 120/66 39.47 (13.71) 76/35/67/8 46/42/37/32/31 64 54.3 42.29 (40.5–44.02) 42.3 75.6 63.2 63.9
325 183/142 42.93 (14.06) 104/84/122/15 117/118/156/72/(n/a) 163 16.3 45.56 (44.36–46.76) 48.1 82.5 76.0 68
CLE/SLE/GE = cryptogenic localisation related epilepsy/symptomatic localisation related epilepsy/generalised epilepsy, CI = confidence interval. a The differences between mono and polytherapy were statistically significant. b Symptoms were reported as always or sometimes being a problem.
effects of AEDs were very common in our study, which further supports pre-existing evidence.4,12,13 Our observation that polytherapy causes more side effects than monotherapy was consistent with the results of Namazi et al.14 and Haag et al.1 In addition, Thomas et al.12 showed that polytherapy was associated with lower quality of life while Haag et al.1 implicated worse employment opportunities in patients on multiple AEDs. In contrast, a single randomised controlled trial (RCT) failed to show any significant difference,15 however, patients were only on one or two old drugs (CBZ versus CBZ and VPA), whereas in our study patients were on numerous combinations typically including at least one new AED (Table 1). It is also worth noting that in our study the LAEP scores in the polytherapy group were often above 45, which is considered intoxication according to Gilliam et al.7 The mean LAEP was >45 in the polytherapy group. The three most common symptoms reported in our study were all central nervous system (CNS) related and included: tiredness, memory problems and difficulty concentrating. The frequencies of reported AE were very high in both polytherapy and monotherapy, although higher in polytherapy. More than 80% in the polytherapy group and more that three quarters in the monotherapy group complained about tiredness, more than three quarters in the polytherapy group and almost two thirds of patients complained about memory problems and about two thirds in both groups complained about difficulties concentrating as always or at least sometimes being a problem. Our data is in keeping with the results of Carpay et al.,5 who reported almost 60% of patients had CNS related AE. Depression and uncontrolled epilepsy were identified as confounding factors.11,13 A higher prevalence of depression in patients on AED than in control subjects may explain the higher LAEP scores in patients on AED compared to controls but is unlikely to explain the higher LAEP scores in polytherapy compared to monotherapy because the depression rates were very similar in poly and monotherapy (48.7% and 42.3%, respectively). Uncontrolled epilepsy in the polytherapy group may have affected the result. Nevertheless, our data highlights the burden of AED. Doctors should resist the temptation to over-treat patients. However, any symptom should not automatically be regarded as an AE of AED in patients with depression and uncontrolled epilepsy. Patients should be encouraged to take AED regularly as non-adherence may be associated with an increased mortality unless it is certain that symptoms are caused by the AED.16 In addition to our main comparison of poly and monotherapy we performed a subgroup analysis looking for differences in different AED. The result should be interpreted with caution but showed interesting trends. In our study CBZ (n = 46, mean LAEP score 44.83, CI 41.68–47.97) was the least well tolerated
monotherapy AED but the confidence intervals overlapped with other AED used in monotherapy. The LAEP score of CBZ in combination with LEV (n = 24, mean = 44.08, CI = 39.83–48.32) was not higher than in CBZ monotherapy. Interestingly CBZ with LTG had a lower mean LAEP (n = 5, mean = 40.00, CI = 26.42–53.57) than CBZ in monotherapy but the numbers were too small to draw any firm conclusions. We showed a trend for LTG having less AE but this did not reach significance, potentially because of the small numbers. According to the SANAD trial LTG is better than CBZ largely because of the better AE profile of LTG.17 Brodie et al. also reported that LTG is better tolerated than CBZ.18 Our approach to use a self-referral register to assess possible AE of AED has a number of limitations. Recorded symptoms are reported by patients and have to be taken on trust. The data in the register may be biased towards more severe cases. Controls were not matched to cases and the mean age in controls was lower than in patients on AED. Polytherapy patients had more severe epilepsy than monotherapy in our study, frequent seizures were likely to be a confounding factor. In addition, there was a trend for higher AED doses in polytherapy than in monotherapy. There are numerous possible combinations for polytherapy. In the current analysis the numbers for each combination were too small to be certain that there are differences between the polytherapies. We hope that with increasing numbers of patients we will be able to provide more robust data on individual combination therapies. The register cannot replace a RCT. Having said this, we think that a register adds to the body of evidence of the burden on AED. We think that the information from the register was valuable and perhaps even more applicable because the AED used reflected current clinical practice. In summary, polytherapy had significantly higher LAEP scores than monotherapy. This should be discussed with the patient before a second AED is added. Conflict of interest statement None of the authors have any conflicts of interest to disclose. Acknowledgements The UKAED Register has been kindly supported with a grant from Epilepsy Action. We would like to thank Carol Chadwick for proof reading the paper. References 1. Haag A, Strzelcyk A, Bauer S, Kuhnem S, Hamer HM, Rosenow F. Quality of life and employment status are correlated with antiepileptic monotherapy versus polytherapy and not with use of ‘‘newer’’ versus ‘‘classic’’ drugs: results of the ‘‘Compliant 2006’’ survey in 907 patients. Epilepsy & Behavior 2010:618–22.
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