Epilepsy Research (2014) 108, 902—908

journal homepage: www.elsevier.com/locate/epilepsyres

Drug treatment in patients with newly diagnosed unprovoked seizures/epilepsy Linnéa Karlsson a,∗, Björn Wettermark a,b, Torbjörn Tomson c a

Public Healthcare Services Committee Administration, Box 17533, SE-118 91 Stockholm, Sweden Karolinska University Hospital Solna, Centre for Pharmacoepidemiology, SE-171 76 Stockholm, Sweden c Karolinska Institutet, Department of Clinical Neurosciences, SE-171 77 Stockholm, Sweden b

Received 11 June 2013; received in revised form 27 January 2014; accepted 16 March 2014 Available online 27 March 2014

KEYWORDS Epilepsy; Seizures; Drug utilization; Prescribing; Antiepileptic drugs

Summary Purpose: The objective of this study was to analyze drug treatment in patients with newly diagnosed unprovoked seizures/epilepsy in a population-based cohort in Stockholm, Sweden. Method: Clinical data from the Stockholm Incidence Registry of Epilepsy was cross-linked with drug dispensing data from the Swedish Prescribed Drug Register to analyze drug treatment in patients diagnosed with unprovoked seizures between 2006 and 2008. Specific questions addressed were the use of other medications at seizures onset, the proportion of patients initiated on different antiepileptic drugs (AEDs) within one year after inclusion, and the extent of switching between different AEDs during the first year. Results: In total 367 patients were included. More than 50% had other medications prescribed at date of first seizure. All together, 262 patients received an AED within one year and 257 patients (98%) were initiated on monotherapy. One year after first prescription, 147 patients (56%) remained on the initially prescribed AED and 48 patients (18%) had switched to another AED. Among the remaining patients, 29 (11%) had died and 38 patients (15%) had discontinued AED treatment. Conclusions: A majority of all patients with epilepsy receive treatment within one year. Many patients use other medications and several of them are related to known comorbidities and can also be involved in drug—drug interactions. Nevertheless, most patients remained on the same AED at the end of the first year. © 2014 Elsevier B.V. All rights reserved.

∗ Corresponding author at: Public Healthcare Services Committee Administration, Department of E-Health and Strategic IT, Box 17533, SE-11891 Stockholm, Sweden. Tel.: +46 8 123 135 84. E-mail addresses: [email protected] (L. Karlsson), [email protected] (B. Wettermark), [email protected] (T. Tomson).

http://dx.doi.org/10.1016/j.eplepsyres.2014.03.004 0920-1211/© 2014 Elsevier B.V. All rights reserved.

Drug treatment in patients with newly diagnosed unprovoked seizures/epilepsy

Introduction Treatment options for patients with epilepsy have increased dramatically with the introduction of several new antiepileptic drugs (AEDs) to the market during the last 20 years (Bialer et al., 2013; Dichter and Brodie, 1996). Simultaneously randomized management studies have assessed different strategies for the treatment of patients with newly diagnosed epilepsy, in particular regarding the pros and cons of early vs. deferred AED treatment (Leone et al., 2006; Marson et al., 2005). These advancements have created opportunities for more rational and individualized treatment strategies in early epilepsy, but also difficulties in selecting among all available options. These challenges in finding the optimal treatment are augmented by comorbidities, concomitant medication, age- and gender specific issues as well as the diversity of the epilepsies. Several different evidence based guidelines have been developed to assist the physician with recommendations for the management of patients with newly diagnosed seizures (Glauser et al., 2013; NICE, 2004; SIGN, 2003). However, population based data on how patients with newly diagnosed seizures are treated are scarce. The objective of this study was to examine pharmacological treatment of patients with newly diagnosed unprovoked seizures and epilepsy in a defined part of the northern region of Stockholm, Sweden. Specifically, we sought to analyze current use of other prescribed drugs at the time of onset of the seizure disorder, the proportion of patients initiated on different AEDs, and the course of AED treatment during the first year after seizure onset.

Methods This study utilized the Stockholm Incidence Registry of Epilepsy (SIRE) to identify a study population of patients with newly diagnosed unprovoked seizures or epilepsy. SIRE is a population based registry aiming at including all incident cases with an unprovoked first seizure or epilepsy in Northern Stockholm. Details of the SIRE methodology have been presented before (Adelow et al., 2009). The registry has been operational since September 2001 and has included nearly 2000 patients up to December 2008 with individual information on the date of the index seizure, defined as the first seizure that prompts the patients to seek medical advice. Potential cases have been identified through multiple methods; medical record screening in specific hospital units (including outpatient clinics), networks of health care professionals, emergency room services, and review of requests for electroencephalography (EEG). All information in SIRE is based on information recorded in relevant medical records during the first six months following the index seizure. Potential cases have been validated and classified by the research team of SIRE based on data obtained from the medical charts. Each case included in the present study population has been classified as definite first unprovoked seizure or definite epilepsy (two or more unprovoked seizures up to the six months’ time limit from the index seizure). For the present analysis, the date of the index seizure was considered as date of inclusion in the study. We included all validated cases in SIRE who had an index seizure

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between 1 January 2006 and 31 December 2008 (n = 398). Patients who had been dispensed AEDs before the index date were excluded (n = 31) leaving 367 patients, our study population for the analysis. SIRE includes among other things information on patients’ age and gender, date of the index seizure, classification of seizure type, and classification of the epilepsy syndrome. Information about drug treatment was obtained from The Swedish Prescribed Drug Register (SPDR) (Wettermark et al., 2007). Established in 2005, this database contains complete data on all drugs dispensed in Sweden regardless of reimbursement status. Included variables are patient’s age, and gender, prescribed and dispensed drugs classified according to ATC codes, date of prescribing and of dispensing, and the prescriber’s speciality. Individualized data on dispensed prescription drugs was linked to clinical data in our SIRE study population by using the unique personal identity number assigned to each Swedish resident (Ludvigsson et al., 2009). To assess the use of medications taken at the time of each patient’ index seizure, all prescriptions dispensed to patients during 90 days prior the day of the index seizure were identified. According to Swedish reimbursement regulations, the maximum quantity of drugs allowed to be dispensed each time is for 3 months of supply and therefore this period prior to index date was applied to provide a valid estimate of current use of prescribed medications, for chronic as well as short-term treatment. The day of the first dispensed prescription of an AED after the index seizure was considered as the day of starting treatment. For each patient, the number of days from index seizure to first dispensed prescription of an AED was calculated. The cumulative proportion of patients with a dispensed prescription of an AED within a year after the index seizure was calculated. A dispensed prescription of an AED during the period 300—420 days after the first prescription of an AED was considered as current use of AEDs one year after treatment initiation. This period of time covers a current use of a prescription. For each patient, the number of days from first dispensed prescription of an AED was calculated, and the latest dispensed AED at 300—420 days was compared to the first AED. Discontinuation of AED treatment was defined as no dispensed prescription of AED during the time period 300—420 days after the first prescription. Switches of AEDs were also analyzed during the same period of time.

Statistical analysis Standard descriptive statistics, such as numbers and proportions with 95% confidence intervals (CI) were used to describe the study cohort and the utilization pattern of the drugs of interest. All analyses were conducted using SAS version 9.2 (SAS Institute, Cary, North Carolina, USA) and Microsoft Excel.

Ethical considerations The Ethics Committee at Karolinska Institutet, Stockholm, Sweden, approved this study. No individual informed consent was obtained since this is a registry study in which no

904 Table 1 (n = 367).

L. Karlsson et al. Demographic data of the study population Cases n (%)

Current use of other medications at time of index seizure

individuals can be identified. All data were anonymized after record-linkage with no possibility of identifying an individual patient.

Out of the 367 patients with newly diagnosed single unprovoked seizure or epilepsy 187 (50.9% (CI 45.8—56.1%)) were dispensed other medications during a period of three months prior to the index seizure. Antihypertensive agents were the most commonly used drug class among both men and women, in 28.9% (CI 24.2—33.5%) of the study population (Fig. 1). Opioids (N02A) were used by 24.5% (CI 20.1—28.9%) of the patients and the most commonly used opioid was tramadol (10.1% (CI 7.0—13.2%)). Among the six most commonly prescribed drug classes, all were more frequently used by women. The largest gender difference was found for antidepressants (N06A), 23.9% in women and 10.8% in men, difference 13.1% (CI 5.3—21.0%). The average number of prescribed drugs per patient at time of the index seizure was 1.9 for patients 0—15 years old (2.2 for boys and 1.6 for girls), 3.8 for patients 16—49 years old (3.7 for men and 3.9 for women), 5.0 for patients 50—64 years old (4.7 for men and 5.3 for women) and 6.1 for patients 65 years and older (5.0 for men and 7.9 for women).

Results

Time to first prescription of an AED

Three hundred and sixty seven patients with newly diagnosed single unprovoked seizures or epilepsy included in SIRE between Jan 1, 2006, and Dec 31, 2008 were previously unexposed to AEDs and included in the present analysis (Table 1). The median age at inclusion in SIRE was 33 years, range 0—87 years. The majority of patients (54.5%) did not have a clear identified cause of their seizure disorder. Twenty nine patients died during the study period and the most common causes were malignant neoplasm of brain (n = 13) and secondary malignant neoplasm of brain and cerebral meninges (n = 4).

Overall, 262/367 (71.4% (CI 66.8—76.0%)) of the study population had a dispensed prescription of an AED within the first year after the index seizure. Among patients with epilepsy (more than one unprovoked seizure at inclusion), 206/242 (85.1% (CI 80.6—89.6%)) were prescribed an AED. Compared with 56/125 (44.8% (CI 36.1—53.5%)) with single seizures. The cumulative proportion of cases prescribed an AED over time is illustrated in Fig. 2. By day 75, 183/367 (49.9%) had received an AED. Fifty percent of patients with epilepsy (121/242) had received their first AED within 44 days.

Gender Men Women

204 (55.6) 163 (44.4)

Age group (years) 0—16 17—64 ≥65

138 (37.6) 170 (46.3) 59 (16.1)

Diagnosis Epilepsy Single unprovoked seizures

242 (65.9) 125 (34.1)

Figure 1 Current use of other medications at time of index seizure. The eleven most commonly prescribed drug classes in the study population at time of the index seizure (n = 367). Antihypertensive agents include diuretics, beta blockers, calcium channel blockers, agents acting on the renin-angiotensin system. GORD = gastro-esophageal reflux disease. *Statistically significant difference (P < 0.05).

Drug treatment in patients with newly diagnosed unprovoked seizures/epilepsy

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Figure 2 Time to first antiepileptic drug. Cumulative proportion of patients with a first dispensed prescription of an AED over the first 365 days after index seizure, sorted by total study population (n = 367), patients with epilepsy (n = 242) and patients classified with single seizure six months after index seizure (n = 125).

First AED Almost all patients (257/262) with a dispensed prescription of an AED were initiated on monotherapy. The types of prescribed AEDs are given in Table 2. Carbamazepine was the most frequently initially prescribed AED to both women and men, 47/119 (39.5% (CI 30.7—48.3%)) and 57/143 (39.9% (CI 31.8—47.9%)), respectively. Valproate was prescribed more to men, 38/143 (26.6% (CI 19.3—33.8%)), than women, 20/119 (16.8% (CI 10.1—23.5%)), while lamotrigine was prescribed more to women, 20/119 (16.8% (CI 10.1—23.5%)), than men, 13/143 (9.1% (CI 4.4—13.8%)). The gender differences were not significant.

Use of an AED one year after first dispensation of an AED Changes from initial AED treatment after one year are presented in Table 3. One year after the first AED was dispensed, 195/262 (74.4% (CI 69.1—79.7%)) patients were still on AEDs, 29 patients had died and the remaining 38 patients had no AED. In total 147/262 (56.1% (CI 50.1—62.1%)) had the same AED as initially prescribed. Switches occurred in 48/262 (18.3% (CI 13.6—23.0%)). Patients diagnosed with epilepsy accounted for the majority of the switches, 45/48 (93.8% (CI 86.9—100.6%)). There were no significant differences in switches between men 29/143 (20.3% (CI 13.7—26.9%)) and women 19/119 (16.0% (CI 9.4—22.5%)). A third of the females receiving valproate switched to another AED or discontinued treatment, 6/20 (30.0%), while the proportion for men was 7/38 (18.4%). More women discontinued drug treatment, 20/119 (16.8% (CI 10.1—23.5%)), compared to men, 18/143 (12.6% (CI 7.2—18.0%)), but the difference was not significant. The highest proportion of patients who discontinued their initial drug treatment was patients taking vigabatrin, 3/7 (42.9%) followed by carbamazepine. Of 47 women initially

prescribed carbamazepine, 12 discontinued the treatment (25.5%), while 9/57 men discontinued carbamazepine (15.8%). Among children, switches occurred in 15/92 (16.3%) patients and 13/92 (14.1%) children discontinued treatment.

Discussion This study describes in a population-based cohort AED treatment during the first year after seizure onset. As expected, the majority of patients with recurrent seizures were initiated on monotherapy. At the one year follow-up, more than half of the patients (56.1%) remained on the first prescribed AED despite the clear risk of pharmacokinetic interactions with concomitant medication. This suggests that physicians were able to manage these potential interactions. Among those still alive; 14.5% had discontinued their AED treatment, whereas 18.3% had switched to another AED. Vigabatrin was the most commonly discontinued or switched AED which is likely explained by its narrow indication and short term use in infants. It was not possible to ascertain whether switches were due to poor tolerability, lack of efficacy or other reasons, but previous studies have reported that only 50% of patients with newly diagnosed epilepsy achieve seizure control remain on the first prescribed AED (Kwan and Brodie, 2001). Our data also show that the AED treatment decisions may be complicated since prescriptions of other medications at the time of seizure onset were common. The average number of prescribed drugs in men was 4.1 and 4.7 in women (all ages) and even higher among the elderly. We do not have prescription data from an age and gender matched control group, but prescriptions of many drug classes were more prevalent in our study population compared with available data from the general population in Stockholm in 2008 (Swedish National Board of Health and Welfare, 2013; Wettermark et al., 2010); 28.9% vs. 6.9% for

25

1

61 53 1 1 39

1 1

3 4 1 4 2

1

65

1

19

1

3 1 2 5 4

11 8 1 11 5 36 15 4

32 12 7 1 7 1 10 15 8 11 4 3 13 10

Carbamazepine Valproate Lamotrigine Oxcarbazepine Levetiracetam Phenytoin Vigabatrin Phenobarbital Topiramate Ethosuximide Gabapentin Pregabalin Carbamazepine + valproate Phenytoin + levetiracetam + valproate Phenobarbital + clonazepam + gabapentin Phenobarbital + topiramate Lamotrigine + oxcarbazepine + clonazepam Total

Men >65 years Women >65 years Men 17—64 years Women 17—64 years Boys 0—16 years Girls 0—16 years

Age and gender distribution of the first antiepileptic drug. Table 2

104 58 33 22 15 8 7 6 1 1 1 1 1 1 1 1 1 262

L. Karlsson et al. Total

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antihypertensive agents, 24.5% vs. 7.9% for opioids, 20.7% vs. 8.2% for hypnotics and sedatives, 16.6% vs. 7.1% for antidepressants, 10.6% vs. 5.1% for anxiolytics, 8.7% vs. 1.5% for neuroleptics. Some of these drug classes reflect known etiologies for epilepsy, such as stroke and dementia. Others are likely related to comorbidities of epilepsy such as depression, psychosis and anxiety disorders (Adelow et al., 2012). The use of opioids (morphine, oxycodone, fentanyl, codeine, ketobemidone, dextropropoxyphene and tramadol) and other analgesics is more difficult to explain and prompt further studies. Of special interest is the frequent use of tramadol, since this drug is known to increase the risk of seizures (Talaie et al., 2009). The inclusion criterion in SIRE is unprovoked seizures, so patients with seizures exclusively provoked by e.g. tramadol should not be included in our study population. Its frequent use in our cohort of patients with a predisposition to generate epileptic seizures is nevertheless cause for concern. The high prevalence of other prescribed drugs highlights the complexity of the pharmacotherapy in patients with new onset seizures. Selection of drug, titration and dose need not just to consider evidence of efficacy for the patients’ seizure disorder, but also take into account potential pharmacodynamic and pharmacokinetic interactions (Patsalos and Perucca, 2003a,b) as well as adverse effects profiles of specific AEDs in relation to existing comorbidities. The fairly frequent switches and discontinuation of AEDs during the first year might to some extent be related to such interaction although we lack information on reasons for switching. A previous study based on a large US commercial health care database reported a median of one AED regimen change in the first year of treatment with polytherapy from onset as the major risk factor for a change (Cunnington et al., 2011), but this study did not analyze switches in relation to concomitant medication or type of AED. Patients who had experienced more than a single seizure at the time of inclusion appeared to receive their first AED earlier than patients with single seizures, which is expected (Perucca and Tomson, 2011). It is likely that the delayed start of AED treatment in the single seizure group was prompted by seizure recurrence later than six months after the index seizure. Information of such late recurrences is not recorded in SIRE. The observed latency between the index seizure and initiation of treatment (median 44 days among those with epilepsy) can be explained by several factors. First, the date of the index seizure was determined by the research group based on the medical records, and might not always be the date when the patients first sought medical advice. Second, treatment could be delayed by the time it takes to complete the work up (e.g. EEG, neuroimaging, and referral to a neurologist or neuropediatrician who usually initiate the treatment). Third, physicians may prefer to offer their patients more than one consultation before initiating medication to discuss the pros and cons of treatment with the hope to enhance long term adherence to medication. Finally, some patients may collect their medication with some delay after receiving their prescription. About a fifth of the total cohort did not receive any medication for their seizures. This can be compared to the National General Practice Study of Epilepsy (NGPSE) study, where about a quarter did not receive medication for their seizures (Lhatoo et al., 2001).

Drug treatment in patients with newly diagnosed unprovoked seizures/epilepsy Table 3

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Characteristics of antiepileptic drug treatment one year after the first dispensed antiepileptic drug.

Initially prescribed AED

Total (n = 262)

Continued with the same AED n (%)a

Switched to another AED n (%)

Discontinued n (%)

Carbamazepine Valproate Lamotrigine Oxcarbazepine Levetiracetam Phenytoin Vigabatrin Phenobarbital Topiramate Ethosuximide Gabapentin Pregabalin Carbamazepine + valproate Phenytoin + levetiracetam + valproate Phenobarbital + clonazepam + gabapentin Phenobarbital + topiramate Lamotrigine + oxcarbazepine + clonazepam

104 58 33 22 15 8 7 6 1 1 1 1 1 1 1 1 1

51 (49.0) 36 (62.1) 25 (75.8) 15 (68.2) 9 (60.0) 3 (37.5) 0 (0.0) 2 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100.0) 0 (0.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0)

16 (15.4) 7 (12.1) 5 (15.2) 3 (13.6) 3 (20.0) 4 (50.0) 4 (57.1) 3 (50.0) 1 (100.0) 1 (100.0) 1 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

21 (20.2) 6 (10.3) 3 (9.1) 4 (18.2) 1 (6.7) 0 (0.0) 3 (42.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

a

Percentage of those initially prescribed AED.

The main strengths in this register-based study are the use of population-based registers. SIRE is one of the largest population-based incident cohorts of newly diagnosed unprovoked seizures and has enabled long-term follow-up studies (Adelow et al., 2009). The seizure diagnosis is validated. All included patients have an individual index date of their seizure and it is possible to prospectively follow the patients over time. There are also certain limitations. SIRE is based entirely on data included in medical records and these are of varying quality. The seizure diagnosis is made by the research team and may not necessarily be identical with the diagnosis or interpretation by the treating physician. The classification of the patients in SIRE is made six months after index seizure, hence we do not know if those classified as single seizure have had a relapse during the one year follow-up in this study. There might also be an under-ascertainment, due to difficulty to keep the network of reporting collaborators efficient. The one year follow-up time of AED treatment is a further limitation of the present analysis as we miss out information about treatment changes after that time window. The Swedish Prescribed Drug Register provides complete coverage of dispensed drugs in the Swedish population (Wettermark et al., 2007). Prescription medications are not biased by self-reporting but the register reports dispensed drugs which does not necessarily equate to drugs taken by the patient. The sensitivity is in general high, but there may be some drugs not dispensed as prescriptions that are taken by the patient, e.g. OTC drugs, sales from Internet pharmacies and prescriptions dispensed abroad. Included patients in this study had no dispensed prescription of an AED before index date. Although various AEDs are approved for indications other than epilepsy; gabapentin and pregabalin are approved for neuropathic pain, valproate and lamotrigine are approved for treatment of bipolar disorder. Therefore, those excluded for AED prescriptions before the

index seizure might have been prescribed AEDs for other indications than epilepsy. Questions may also be raised about the generalizability of our findings to other countries with different health care systems, reimbursements and therapeutic traditions, but this is the case for any cross-country comparison. In conclusion, we found that a high proportion of the study population received treatment within one year and almost all received monotherapy. Many patients also used other medications and several of them are related to known comorbidities. These findings highlight the complex pharmacotherapy in this patient population, and the importance of taking this into account when selecting AEDs, and the need for close monitoring of potential pharmacokinetic and pharmacodynamic drug interactions. The majority of patients had the same AED as initially prescribed one year after the first prescription. However, there were a high number of switches among patients with epilepsy, which indicates the importance of choosing the most appropriate initial AED.

Conflicts of interest Torbjörn Tomson received research grants from GSK, and UCB and has received speaker’s or consultancy fees from GSK, UCB, Eisai, Sun Pharma, and Bial. The other authors have no conflicts of interest.

Acknowledgements We would like to thank Thomas Cars, Public Healthcare Services Committee Administration, Stockholm County Council, for statistical assistance. This study was supported by a grant from the Stockholm County Council (ALF) No. 20110369, and from AFA Insurance Company (No. 090009).

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The objective of this study was to analyze drug treatment in patients with newly diagnosed unprovoked seizures/epilepsy in a population-based cohort i...
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