Antiepileptic drug treatment after an unprovoked first seizure: A decision analysis

Abstract

Objective: To compare the expected quality-adjusted life-years (QALYs) in adult patients undergoing immediate vs deferred antiepileptic drug (AED) treatment after a first unprovoked seizure.

Methods: We constructed a simulated clinical trial (Markov decision model) to compare immediate vs deferred AED treatment after a first unprovoked seizure in adults. Three base cases were considered, representing patients with varying degrees of seizure recurrence risk and effect of seizures on quality of life (QOL). Cohort simulation was performed to determine which treatment strategy would maximize the patient's expected QALYs. Sensitivity analyses were guided by clinical data to define decision thresholds across plausible measurement ranges, including seizure recurrence rate, effect of seizure recurrence on QOL, and efficacy of AEDs.

Results: For patients with a moderate risk of recurrent seizures (52.0% over 10 years after first seizure), immediate AED treatment maximized QALYs compared to deferred treatment. Sensitivity analyses showed that for the preferred choice to change to deferred AED treatment, key clinical measures needed to reach implausible values were 10-year seizure recurrence rate ≤38.0%, QOL reduction with recurrent seizures ≤0.06, and efficacy of AEDs on lowering seizure recurrence rate ≤16.3%.

Conclusion: Our model determined that immediate AED treatment is preferable to deferred treatment in adult first-seizure patients over a wide and clinically relevant range of variables. Furthermore, our analysis suggests that the 10-year seizure recurrence rate that justifies AED treatment (38.0%) is substantially lower than the 60% threshold used in the current definition of epilepsy.

Figure 1. Markov model for immediate and deferred AED treatment

Markov cycle trees for (A) immediate antiepileptic drug (AED) treatment and (B) deferred AED treatment showing different states in the disease course and possible transitions between them. Colors are weighted by the utility (quality-adjusted life-years) associated with each state. Recurrent = recurrent seizure.

Figure 2. Cohort proportions over time for immediate vs deferred AED treatment

Both cohort simulations start at year 0 immediately after a first seizure. (A) In the immediate treatment model, individuals begin in the 2 states of receiving antiepileptic drug (AED) treatment with or without side effects (22% with side effects, 78% without). (B) In the deferred treatment model, all individuals begin in the state of no recurrent seizure and no AED treatment. In subsequent cycles, varying proportions of individuals remain in the same cohort or progress to another state involving recurrent seizures or death. All individuals are in the death cohort by the end of each simulation (year 90).

Figure 3. One-way sensitivity analyses

One-way sensitivity analyses of quality-adjusted life-years (QALYs) for (A) QOL reduction with recurrent seizures, (B) QOL reduction with antiepileptic drug (AED) side effects, (C) annual risk of recurrent seizures without treatment, (D) efficacy of AED, and (E) mortality ratio. Blue and red solid lines indicate how QALY varies with the measurement of interest in patients undergoing the deferred vs immediate AED treatment, respectively, with all other measures held fixed. The green dashed line indicates the measure for base case 1, and the gray dashed line indicates the threshold at which deferred and immediate treatments are equally preferred.

Figure 4. Two- and 3-way sensitivity analyses

(A) Two-way sensitivity analysis indicating the favored decision for patients with differing levels of quality of life (QOL) reduction from recurrent seizures (x-axis) and seizure-associated mortality ratios (y-axis). In all panels, the yellow point marks base case 1, and the blue and red regions delimit the combinations resulting in greater quality-adjusted life-years (QALYs) with deferred vs immediate antiepileptic drug (AED) treatment, respectively. (B) Two-way sensitivity analysis indicating the favored decision for patients with varying risk of AED side effects (x-axis) and risk of recurrent seizures without AED treatment (y-axis). (C) Three-way sensitivity analysis indicating the favored treatment for patients with differing seizure recurrence rate (y-axis), level of QOL reduction from recurrent seizures (individual x-axes within each subplot), and AED efficacy (x-axis spanning all subplots).