Is erenumab an efficient alternative for the prevention of episodic and chronic migraine in Spain? Results of a cost-effectiveness analysis

The course of the disorder was represented by a decision tree with two alternative branches (responders and non-responders), followed by a Markov model comprising two health states (treatment and discontinuation) with cycles lasting 12 weeks (Fig. 1). Model health states were exclusive, i.e. patients could only be in one specific health state at a specific time. Responders were defined as patients with 50% reduction in the number of MMD at week 12, regardless of whether they suffered from EM or CM.

All patients entered the model at treatment initiation and, after the assessment period (12 weeks), their response (i.e. responders or non-responders) to treatment was determined. Patients who responded (responders) could either continue the prophylactic treatment initiated (state: treatment) or discontinue if they had experienced adverse events (state: discontinuation). Patients in the treatment state were assumed to remain in that state until discontinuation due to adverse events. Costs and utilities were assigned based on the number of MMDs at the end of each cycle.

The mortality of the different states was considered similar to that of the general population, adjusted by age and sex, because no additional mortality was associated with migraine [35].

Clinical data of the model were obtained from clinical trials of erenumab (Table 1). For the comparison between erenumab and topiramate in patients with EM, the HER-MES head-to-head study [26] was used. For the CM population, data for erenumab vs placebo were from Tepper et al. [31].

Data available in the HER-MES study [26] and the NCT02066415 clinical trial [31] were used to recalculate the probabilities of the adverse events applied in the model, with adjustments period required for this study (12 weeks). Mean values were weighted based on the sample size of the available studies.

Following discontinuation due to adverse events, data included in the model were obtained from the main clinical trials with erenumab [26, 28, 31]. The topiramate discontinuation values were based on those described in the HER-MES study [26]. For EM, discontinuation probability per cycle was 5.52% for erenumab [26, 28, 31] and 35.57% for topiramate [26]. For CM, discontinuation for placebo was 0.71% and for erenumab was 1.06% [31].

Since the model considered a 10-year time horizon and the selected studies had only short terms, the probability of moving from treatment to discontinuation state after 12 weeks was estimated from the available long-term data and assumed for the 10-year time horizon. This produced a probability of long-term discontinuation for each cycle (12 weeks) of 30.26% (standard error [SE] 0.0177) for placebo [36], 5.1% (SE 0.0112) for topiramate after estimating the increase in discontinuation between weeks 12 and 24 of the HER-MES study [26] and 0.5% for erenumab based on the data of the 5-year extension study [37].

Utility refers to the value that an individual places on a health state: A score of 1 represents the best possible quality of life while a score of 0 represents a state equivalent to death. In this analysis, QALYs were calculated using estimated utilities obtained from the individual data collected from the trials [28, 31], by applying a linear regression based on MMD reduction, and considering the mortality of the general population. Consequently, utilities corresponding to each MMD state of the spectrum analysed (0–28 MMD) were calculated to give a mean reduction in utility per MMD of 0.0176 (SE 0.0035). Patients without migraine showed a utility of 0.85, patients with migraine and < 3 MMD showed a utility of 0.79–0.83, EM patients with < 7 MMD showed a utility of 0.72–0.78, EM patients with ≥ 8 MMD showed a utility of 0.6–0.71, CM patients with < 21 MMD showed a utility of 0.48–0.58, and CM patients with ≥ 21 MMD showed a utility of 0.36–0.46.

Based on the utility by MMD, a utility loss was applied for adverse events [28, 31, 38]. Utility losses applied to each treatment were based on frequency of onset as follows: brain fog -0.097 (SE 0.13), fatigue -0.061 (SE 0.097), exercise intolerance -0.048 (SE 0.092), insomnia -0.048 (SE 0.088), neck stiffness and pain -0.045 (SE 0.077), muscle weakness -0.034 (SE 0.058), sleepiness -0.03 (SE 0.059), constipation -0.029 (SE 0.06), drooping eyelids -0.024 (SE 0.067), respiratory tract infection -0.012 (SE 0.033), paraesthesia -0.012 (SE 0.045), dizziness -0.01 (SE 0.041), dry mouth -0.01 (SE 0.044), injection site pain -0.008 (SE 0.025) and itchiness -0.006 (SE 0.023) [38].

Therapy costs were estimated using approved dosages (dose and frequency of use) and unit costs [39]. Ex-factory prices were used for hospital-dispensed treatments, and retail prices were applied for the remaining treatments, always using the reimbursed price. The corresponding discount according to Spanish Royal Decree 08/2010 [40] was applied.

For acute treatment with triptans, the pharmacological cost was estimated using the weighted average of almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan, as well as the cost of the consumption of aspirin, ibuprofen, ketoprofen, paracetamol, and paracetamol with codeine.

The cost per health state, including hospitalisations, emergency room visits, appointments with specialists or primary care doctors, and concomitant medication (Table 2), was based on the average unit costs of each Spanish autonomous region [41‐57] and the use of resources provided, which were validated by an expert panel comprising specialists in neurology, and hospital pharmacists with knowledge of the disorder. Hospitalisation costs were calculated considering the average cost of a complete stay due to migraine and other headaches (DRG 54) at the neurology unit of the 2020 Minimum Basic Database Set [58], which is an administrative database on hospitalised patients. All costs were inflated to 2023 costs using the Consumer Price Index [59].

For the societal perspective analysis, which corresponds to an alternative scenario, indirect costs, such as absenteeism and presenteeism, were included in the model. Out-of-pocket expenses were not considered as evidence is lacking for this in the field of migraine. The relationship between absenteeism measured by the MIDAS scale [60] and MMD was determined through a regression model, and the same was performed for presenteeism. After determining the volume, the cost of one day of lost work for patients with absenteeism was applied, along with half a day of work for patients with presenteeism [61].

To estimate the daily labour cost, the total monthly wage cost (€2,847.10) [62] was adjusted to 22 working days, considering an unemployment rate of 12.7% [63]. In the sensitivity analysis, the valuation of indirect costs was incorporated using WPAI [64] methodology.

These models are inevitably subject to uncertainty, thus we conducted both deterministic and probabilistic sensitivity analyses, following the recommended guidelines [34]. To evaluate the potential impact of each assigned variable, a univariate analysis was performed, varying the parameters by 20%. The results are presented in a tornado diagram [65]. A univariate sensitivity analysis was also performed using different scenarios (number of treatment failures, absence of prior failure to onabotulinumtoxinA, societal perspective, measurement of absenteeism/presentism). The model was complemented with a probabilistic sensitivity analysis by applying lognormal distributions for odds ratio, beta distributions for probabilities and utility loss, multivariate normal distributions for utilities and for the regressions assessed, and gamma distributions for resource use and discontinuation rates [66]. The probabilistic sensitivity analysis was supported by a 1000-iteration Monte Carlo simulation, which draws random values of the parameters per iteration to provide a theoretical probability distribution. The probabilistic sensitivity analysis results were plotted into a cost-effectiveness acceptability curve [67].

At baseline, patients with EM had an average MMD of 9.44, which decreased to 6.95, 7.23 and 7.42 at 12, 24 and 108 weeks (first two years), respectively, following treatment with erenumab. Patients with EM treated with topiramate had 8.56, 8.65 and 8.86 MMD on average at 12, 24 and 108 weeks. Thus, at 10 years, patients with erenumab would have experienced 877 MDs, while patients with topiramate would have experienced 1,049 MDs (Table 3).

Considering both MD and HRQoL, erenumab displayed an increase in QALYs with respect to topiramate (0.2311 QALYs).

Healthcare costs reached €21,479 and €17,059 for erenumab and topiramate, respectively, and hospitalization accounted for 34% and 25% of their respective overall cost. In addition, the costs per emergency visit were 33% for topiramate and 24% for erenumab. For erenumab, the highest costs came from pharmacological treatment (29%). Considering the societal perspective, the 10-year costs of topiramate amounted to €53,157, whereas those of erenumab amounted to €52,393. The cost reduction with erenumab compared with other alternatives was mainly derived from the costs of absenteeism, which amounted to €13,934 and €16,396 for erenumab and topiramate, respectively. This difference increased upon inclusion of the costs of presenteeism (erenumab €16,979; topiramate €19,703). Thus, indirect costs constituted 59% and 68% of the costs of erenumab and topiramate, respectively.

For the costs and effectiveness at 10 years, the ICER between erenumab and topiramate in the Spanish context was €19,122 per QALY gained and €26 per MD avoided. The loss of quality of life based on MD and the probability of a response had the largest effect on the results based on the univariate sensitivity analysis (Supplementary Material S1). These results were confirmed by the probabilistic sensitivity analysis, indicating a probability of > 50% that erenumab is cost-effective for thresholds > €20,700 compared with topiramate (Fig. 2). From a societal perspective, erenumab would be the dominant alternative versus topiramate because it was more effective in reducing MMD and increasing QALY, with lower associated costs (Supplementary Material S2).

Over the 10-year time horizon, patients with CM treated with erenumab showed a reduction of 568 MMD compared with that of placebo. Hence, at 10 years, patients with a baseline mean MMD of 18.66 would reach a mean MMD of 18.32 with placebo and 13.48 with erenumab. These results translated to 4.5016 and 5.2578 QALYs for placebo and erenumab, respectively (Table 3).

Healthcare costs reached 26,734€ for erenumab and €24,921 for placebo. Hospital stays accounted for 44% of the costs of placebo and 32% of those of erenumab, while the costs per emergency visit were 24% for placebo and 21% for erenumab. Pharmacological treatment represented 22% of the total medical costs for erenumab. Considering the societal perspective, indirect costs were 73% of the total 10-year placebo cost (total costs €92,023) and 65% of erenumab cost (total costs €76,875). This was due to the high costs of presenteeism (€27,079 for erenumab and €35,989 for placebo) and absenteeism (€23,062 for erenumab and €31,113 for placebo).

The ICER between erenumab and placebo in the Spanish context resulted in 2,398€/QALY gained and €3 per MD avoided. From a societal perspective, which added productivity losses to the healthcare system perspective, the use of erenumab would be the dominant therapeutic strategy for patients with multiple preventive treatment failures, as this produced savings of €15,148 and improved effectiveness, measured both in QALYs gained and MD avoided (Supplementary Material S2).

Univariate sensitivity analysis from the healthcare perspective demonstrated that hospital costs, loss of quality of life based on MMD and probability of response to treatments were the greatest influence on the outcome (Supplementary Material S3). However, the ICER was not sufficiently modified in any of the cases to change the conclusion of the analysis. The robustness of the results was confirmed in the probabilistic sensitivity analysis, where the acceptability curve showed that erenumab becomes the option of choice when the willingness to pay per QALY gained exceeds €5,800, a figure well below the €30,000/QALY threshold commonly accepted in Spain [32] (Fig. 2). Scenario analysis showed that erenumab was cost-effective versus placebo, regardless of the number of prior treatment failures or whether patients had an absence of prior failure to onabotulinumtoxinA, with an ICER below €5,000/QALY gained (Supplementary Material S4).