. 2022 Dec 20;43(1):53–84. doi: 10.1002/phar.2748

TABLE 4.

Summary of studies reporting humanistic and economic outcomes

Author (year) Country, study design	Total number of participants	Age (mean ± SD and/or median, IQR)	Intervention and control groups (if applicable)	Number of ASMs at baseline	Humanistic outcome(s) evaluated	Summary of results	Results based on polytherapy
Bardai et al. (2012) ⁴⁴ Netherlands Non‐RCT, case control	3853 (1019 cases vs. 2834 controls) PWE: 12 cases and 12 controls	Cases: 63.5 ± 13.7 Controls: 58.3 ± 14.5 Cases with epilepsy: 60.0 ± 16.0	NA	Reported for PWE only: Monotherapy: Cases: 4 Controls: 10 Polytherapy: Cases: 8 Controls: 2	Odds of SCA associated with epilepsy	Epilepsy was associated increased odds of SCA (adjusted OR 2.9 [95% CI 1.1–8.0], p = 0.034)	No statistical analyses were conducted based on monotherapy vs. polytherapy. Numerically more PWE cases taking polytherapy (8/12, 75%) compared to controls (2/12, 17%)
Bautista et al. (2012) ⁴¹ US Non‐RCT, cohort	108	42	NA	68% on monotherapy and 31% on two ASMs	MMPR	PHB had a higher MMPR (1.04 ± 0.2) compared to other ASMs (p < 0.05) Based on multivariate analysis, dosing frequency, ASM type (old vs. new), and mono‐ vs. polytherapy were independent predictors of MMRP (all p < 0.05)	MMPR for monotherapy was significantly higher compared to polytherapy (0.95 ± 0.25 vs. 0.91 ± 0.2, p = 0.02)
Freitas‐Lima et al. (2013) ⁴³ Non‐RCT, cross sectional	112	38.8 ± 11.8	NA	1 ASM: 8 (7.1%) 2 ASMs: 36 (32.1%) ≥3 ASMs: 68 (60.7%) 4 ASMs: 6 (5.4%)	ASM prescribing patterns (e.g., mean ± SD (range) of ASMs per patient, commonly prescribed ASMs) Evaluation of ASM load: ratio of prescribed daily dose over defined daily dose (PDD/DDD)	ASMs per patient: 2.6 ± 0.7 (range: 1–4) Of 8 patients who received monotherapy, CBZ was the most common (n = 6), then LTG and VPA (n = 1 each) The most common ASM combination was CBZ + CLB + LTG (18/112)	The more ASMs prescribed, the higher the ASM load (r = 0.63, p < 0.01)
French et al. (2014) ²⁷ International RCT	366	Placebo: 39.1 ± 12.5 OXC 1200: 39.1 ± 11.5 OXC 2400: 38.5 ± 11.6	Placebo vs. OXC (1200 or 2400 mg)	1 ASM: Placebo 43 (35.5%) OXC 1200: 36 (29.5%) OXC 2400: 40 (32.5%) 2 ASMs: Placebo: 61 (50.4%) OXC 1200: 68 (55.7%) OXC 2400: 67 (54.5%) 3 ASMs: Placebo: 17 (14%) OXC 1200: 18 (14.8%) OXC 2400: 16 (13%)	(Secondary outcomes) changes in PGIC and QOLIE‐31 scores	PGIC score changes were not significantly different for any OXC group compared to placebo. Mean total QOLIE‐31 and subscale scores did not decrease (i.e., improve) from baseline in any group	All patients were taking multiple ASMs
Kusznir Vitturi et al. (2019) ³⁴ Brazil Non‐RCT, Cohort	82	24.5 ± 5.5	NA	Monotherapy: 41 (50%) Polytherapy: 40 (48.8%)	Medication adherence Obstetrical outcomes (e.g., rates and the type of MCM as documented at discharge from the maternity unit)	Patients who experienced an increase in seizure frequency were more likely to have poor adherence, need increased dose adjustment, and need to add another ASM (p < 0.05 for each factor). Obstetric complications were associated with multiple comorbidities, poor adherence, unsuccessful epilepsy control, and increased seizure frequency (p < 0.05). Five MCMs reported in this cohort	No association between polytherapy and increased seizure frequency (OR 2.0 95% CI 0.8–4.8, p = 0.18). Obstetric complications were also associated with polytherapy (p < 0.05). Of patients who developed status epilepticus (n = 7), five (71%) were taking polytherapy (no statistical analysis). Of the five MCM cases, four (80%) were in the setting of exposure to polytherapy (no statistical analysis)
Pirio Richardson et al. (2004) ³⁸ US Non‐RCT, cohort	35	39.8 (range, 20–63)	NA	All were on polytherapy at the start of the study and were converted to monotherapy	Quality of life, as measured by 10 questions from QOLIE‐31	Compared to polytherapy, patients reported their state of health (question 10) was improved after transitioning to monotherapy (p = 0.0004). Significant improvements in specific QOL parameters included: memory loss, concern over medication long‐term effects, difficulty in taking the medications, and trouble with leisure time activities (p < 0.05)	All patients were transitioned from polytherapy to monotherapy
Remak et al. (2004) ³³ UK Non‐RCT, cohort	125	CLB: 37.3 ± 8.2 GBP: 36 ± 11 LTG: 37 ± 9.8 TPM: 38 ± 12.6 VGB: 35.7 ± 12	CLB, GBP, LTG, TPM, VGB	All patients were on at least one ASM	Humanistic EuroQol EQ‐5D Quality of Life Assessment Schedule (not reported) Economic QALY Patient‐specific cost and utility	Humanistic Compared with baseline, only patients treated with TPM had a significant increase in EQ‐5D utility score (p < 0.05). VGB was associated with a nonsignificant increase, while CLB, GBP, and LTG were associated with nonsignificant declines in EQ‐5D utility scores (p‐values not reported) Economic ICER TPM vs. VGB: £7869/QALY Patients receiving VGB had the lowest mean costs over 6 months, while patients receiving LTG had the highest mean costs over the follow‐up period but was statistically significance (p = 0.52)	Not reported
Sackellarres et al. (2004) ³¹ US RCT	152	Placebo: 36.4 ± 11.3 ZNS: 35.6 ± 12.1	Placebo vs. ZNS	Not reported	(Secondary outcomes) Physician and patient global assessments	Global assessments were completed in 77 (99%) and 74 (100%) in the ZNS and placebo groups, respectively. Physician assessment noted 49 (63.6%) in the ZNS group as improved (slightly or markedly) by treatment comped to 8 (10.8%) in the placebo group (p < 0.001). Among patients, 51 (66.2%) in the ZNS group reported their condition improved with treatment compared to 9 (12.3%) in the placebo group (p < 0.001)	Not reported
Schmidt et al. (1993) ³² European RCT	139	Range: 18–59	Placebo vs. ZNS	Up to three concomitant ASMs (with therapeutic levels prior to study start)	(Secondary outcomes) Physician and patient global assessments	Physicians reported improvements with treatment in 41 (62.1%) in the ZNS group compared to 12 (18.8%) in the placebo group (p < 0.0001). Among patients, 40 (60.6%) in the ZNS group reported their condition improved with treatment compared to 19 (29.7%) in the placebo group (p = 0.005)	Not reported
Sveinsson et al. (2020) ⁴⁵ Sweden Non‐RCT, case control	1275 (255 cases vs. 1148 controls)	Not reported	NA	Cases: 0 ASMs: 46 1 ASM: 113 2 ASMs: 96 Controls: 0 ASMs: 265 1 ASM: 483 ≥2 ASMs: 400	Associations between SUDEP and medications (model three reported)	OR of SUDEP and: No ASMs vs. specific ASM monotherapy: LEV 0.10 (0.02–0.61) All other monotherapies were not statistically significant Nonadherence mentioned in the medical record: Yes 2.75 (1.58–4.78)	OR of SUDEP based on ASM therapy: Monotherapy 0.79 (0.44–1.41) Polytherapy 0.48 (0.26–0.09) 2 ASMs 0.59 (0.31–1.12) ≥3 ASMs 0.31 (0.14–0.67)
Xu et al. (2006) ⁴⁰ US Non‐RCT, cross sectional	201	44.2 ± 12.5	NA	2 ASMs: 139 (69.2%) 3 ASMs: 49 (24.4%) 4 ASMs: 12 (6.0%) ≥5 ASMs: 1 (0.5%)	Quality of life (QOLIE‐10, EQ‐5D) Sleep score (MOS Sleep Problems Index, nine‐item scale)	Quality of life QOLIE‐10 total score: 60.8 (20.6) EQ‐5D health state valuation: 0.64 (0.35) Sleep scores MOS Sleep Problems Index Score: 36.2 (20.8) (For reference, the average score for the general US population is 26.) Comparison among subjects with and without diagnosed sleep disturbance Worse mean QOLIE‐10 scores (55.2 (20.6) vs. 63.7 (20.1); p = 0.006) Lower EQ‐5D health state score (0.49 vs. 0.71; p < 0.001) Worse MOS scores (46.8 (19.7) vs. 31.1 (19.2); p < 0.001) Among patients taking two ASMs Better MOS Sleep Problem Index scores for those taking second generation ASMs only compared to those who were not (28.9 (17.1) vs. 37.4 (19.7), respectively; p = 0.021)	All patients were taking multiple ASMs No significant difference in the mean MOS Sleep Problems Index Score based on number of ASMs (p = 0.202); however, patients taking 4+ ASMs reported higher scores compared to patient taking two or three ASMs
Yeh et al. (2021) ⁴² Taiwan Non‐RCT, case control	134	Refractory: 36.7 ± 12.1 Medically controlled: 34.9 ± 11.6	NA	Refractory: 1 ASM: 5.30% 2 ASM: 60.5% 3 ASMs: 23.70% Medically controlled: 1 ASM: 53.1% 2 ASMs: 27.10%	Sleep scores (PSQI, ESS, SF36) Sleep architecture (polysomnography results)	PSQI score Mean PSQI score for entire cohort: 7.67 ± 4.41 PSQI score >5 for refractory vs. controlled, respectively: 78.6% vs. 64.9% (p = 0.1243) ESS score Mean ESS for entire cohort: 6.72 ± 3.33 ESS score > 10 for refractory vs. controlled, respectively: 20% vs. 16.7% (p = 0.6526) Sleep architecture for refractory vs. controlled, respectively REM latency (in minutes): 152.18 ± 84.13 vs. 117.23 ± 61.89, p < 0.01 REM sleep %: 13.52 ± 6.097 vs. 16.24 ± 6.103, p < 0.05 All other parameters were not statistically significant	Not reported

Abbreviations: ASM, antiseizure medication; BID, twice daily; CI, confidence interval; EQ‐5D, EuroQol‐5 dimensions; ESS, Epworth Sleepiness Scale; ICER, incremental cost‐effectiveness ratio; MCM, major congenital malformations; MMPR, mean medication possession ratio; OR, odds ratio; PGIC, Patient Global Impression of Change; PSQI, Pittsburgh Sleep Quality Index; PWE, people with epilepsy; QALY, quality‐adjusted life years; QOLIE‐10, quality of life in epilepsy‐10; QOLIE‐31, quality of life in epilepsy‐31; SCA, sudden cardiac arrest; SF36, Short form survey; SUDEP, Sudden Unexpected Death in Epilepsy; TID, three times daily; MOS, Medical Outcomes Study.

Abbreviations for ASMs: BRV, brivaracetam; CBZ, carbamazepine; CLB, clobazam; ESL, eslicarbazepine acetate; GBP, gabapentin; LCS, lacosamide; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PER, perampanel; PGB, pregabalin; PHB, phenobarbital; PTH, phenytoin; TPM, topiramate; VGB, vigabatrin; VPA, valproate; ZNS, zonisamide.