This is the first study presenting the costs savings associated to the sustained preventive treatment of migraine in a large sample managed in a real world setting of the European Union. Persistence to traditional oral migraine prophylaxis was poor, especially in the first half-year, and migraine-associated costs were higher for non-persistent patients. In this study, we compared the cohort of persistent and non-persistent patients and analyzed the risk of preventive treatment discontinuation according to several factors.
When indicated, preventive treatment and persistence to it can help achieve the therapeutic goals and have economic benefits for public healthcare systems [9, 14, 18, 19]. Our results point towards the same direction. Non-persistent patients require more medical assistance and days of sick leave compared with persistent ones. The costs also increased when patients dropped out of treatment, with a mean total cost difference of €622 per patient per year. In Europe and the USA, indirect costs represent most of the economic burden associated with migraine, which is mainly derived from impairments in productive work [8]. In our sample, indirect costs in each study group represented approximately half of the total expenditure, which coincides with the Spanish 2018 atlas of migraine [28, 29]. Regarding healthcare direct costs, our estimated expenses (€1,127 to €1,477 depending on treatment persistence/non-persistence, respectively) also fall in between reference ranges for episodic (€964 - €1,092 per patient/year) and chronic migraine (2,670–3,847 per patient/year) in Spain [28, 29]. In most European countries, active workers, pensioners or people perceiving unemployment benefits as well as their relatives are entitled to full health cover, an allowance for temporary incapacity and part or complete reimbursement of public medical prescriptions [31]. Thus, the aforementioned cost difference between patient groups has a direct impact on the public purse, which represents an important factor to be considered when comparing health economic studies across countries, especially those without a similar public system. These data support the claim that an association between preventive treatment discontinuation and subsequently increased medical care and economic burdens. Hence, the application of healthcare policies reinforcing the use of prophylactic therapies that may contribute to alleviate them.
Our results on persistence to preventive treatment are more optimistic than those presented by Hepp and colleagues, who found 6- and 12-month persistence rates to oral preventive medication of 25% and 14%, respectively [25]. Nonetheless, we suspect that these differences may be at least partially explained by the inclusion of patients with chronic migraine only and the definition of persistence used (≤ 30 days between consecutive prescriptions), which excluded the patients that switched [25]. In our study, patients that switched their medication within 60 days after the previous prescription were also considered persistent apart from the ones who maintained the same line of treatment. Another pooled analysis of observational studies found that persistence to propranolol, amitriptyline, and topiramate can range from 19–79% at 6 months, and 7–55% at 12 months, which could also be explained by methodological discrepancies [16]. In sum, although results from different studies need to be interpreted cautiously, our conclusions are in line with the available evidence on migraine preventive treatment. Overall, it shows poor adherence and persistence to migraine prophylaxis.
Regarding the type of medication, prescription preferences in different countries may be subject to multiple variables such as local practice, availability, costs and reimbursement policies. For example, flunarizine was used as the first preventive treatment in almost a tenth of patients in our study, whereas in the US and Japan it is not available by prescription. Also, we found that the antidepressant amitriptyline was the most common prescription for migraine prophylaxis, though it was ranked level B of evidence for efficacy (i.e. probably effective) by the American Academy of Neurology and the American Headache Society, and it has been recently recommended as a second-line medication by several European medical societies [12, 32]. In contrast, topiramate and propranolol, which are the front-line recommended therapies for migraine prevention among others [12, 32], ranked second and third in our list. Finally, the fact that only 58% and 28% of patients in each study group received symptomatic treatment with NSAIDs and triptans is intriguing and may be a sign of poor disease management since the expected percentages fell well above 90% and 80%, respectively. Nonetheless, our results coincide with a national survey that assessed the treatment preferences for migraine among Spanish neurologists carried out in 2018 [28, 29]. In the case of botulinum toxin, the number of patients that may have received it upon oral preventive treatment failure was unknown since it is not currently dispensed by community pharmacies in our country. Other types of treatments that we may have disregarded are the over-the-counter ones and those prescribed by paper and/or private medical care.
When characterizing the profile of our study population, we observed that almost half of our patients commonly experienced psychiatric comorbidities such as generalized anxiety disorder and depressive syndrome. According to previous works, they can interfere with migraine evolution and treatment outcomes [33–35], so special consideration should be taken towards them, not only as reactive symptoms but also as migraine chronification.
For episodic migraine, Spanish official guidelines recommend maintaining migraine preventive treatment for six months, with a minimal period of three months and a maximum that depends on individual clinical features [36]. Other European and American recommendations suggest a minimum trial period of 2–3 months to achieve efficacy [2, 12]. Therefore, the first half-year of our study was key. After six months, only a third of migraine patients were still on preventive treatment and the highest dropout rate was observed during the first three months.
The MSM results showed that medication discontinuation could be state-dependent, as suggested by the different HR values obtained from each treatment line. In this sense, no other previous works in migraine patient management have addressed differential discontinuation risks across therapeutic lines and how patients transition among them. In this work, we have observed that the probability of abandoning the treatment was higher during the first line compared to the second one. The same trend was observed for the treatments administered in third line or higher, although it did not reach statistical significance, probably due to the lower number of patients in this category. This different discontinuation risk may have been related to different plausible therapeutic behaviours: 1) Patients followed tapered withdrawal for some time according to guideline recommendations [2, 10, 12] or, on the contrary, 2) patients permanently discontinued their medication due to poor efficacy, safety, tolerability or satisfaction with the treatment. In previous studies, lack of efficacy and tolerability/safety issues were the most frequent reasons for discontinuation according to previous works [14, 16, 18, 37]. However, other reasons, such as patients lost to follow-up or patient’s choice (including reasons related to cost/insurance, access, travel, etc.), have been reported too [14, 16, 37], which should be revisited to increase persistence rates. Our results suggest that patients taking their first oral medication may be especially susceptible to long-term discontinuation, and increasing the awareness on the possibility of a second, third or even a fourth line of therapy may increase the persistence rate. Finally, more data regarding clinical characteristics may be needed to investigate whether patients that cycle through different lines of treatments suffer from a more severe migraine and a higher need to improve their symptoms.
Despite the high number of patients analyzed, the retrospective nature of this work imposes some limitations such as the disease underreporting, other non-reported comorbidities by the patients or any other missing data. Regarding a possible bias in the estimation of the discontinuation risk, subjects in second or higher line of therapy, do not have the chance to stay on treatment as long as first line, resulting in a decrease of the HR. However, we have observed that most of the discontinuations happened within the first 6 months leaving as much time for at least a second line therapy as it was for the first line.
Future studies should address these limitations and include CGRP antagonists for migraine prophylaxis, which were marketed in Spain after our study period [38]. Despite their high cost and restricted availability, their ease of use (monthly or quarterly administration) is expected to increase treatment persistence [2, 11, 39].