Health Technology Assessment (Oct 2024)
Preventive drug treatments for adults with chronic migraine: a systematic review with economic modelling
Abstract
Background Chronic migraine is a disabling condition, affecting 2–4% of adults globally. With the introduction of expensive calcitonin gene-related peptide monoclonal antibodies, it is timely to compare the clinical effectiveness and cost-effectiveness of preventive drugs for chronic migraine. Objective To assess the clinical effectiveness and cost-effectiveness of medications used for chronic migraine through systematic reviews and economic modelling. Eligibility criteria Randomised controlled trials of drug treatments for efficacy with > 100 participants with chronic migraine per arm; for adverse events > 100 participants with episodic or chronic migraine per arm. Previous economic analyses of preventive drugs for chronic migraine. Data sources Eight databases. Reviews methods Systematic reviews, network meta-analysis and economic modelling. Outcomes Monthly headache days, monthly migraine days, headache-related quality of life, cost-effectiveness. Results We found 51 individual articles, reporting 11 randomised controlled trials, testing 6 drugs (topiramate, Botox, eptinezumab, erenumab, fremanezumab, galcanezumab), versus placebo, on 7352 adults with chronic migraine. Calcitonin gene-related peptide monoclonal antibodies, Botox and topiramate reduced headache/migraine days by 2.0–2.5, just under two, or by less than 1.5 days per month, respectively. In the network meta-analysis, eptinezumab 300 mg and fremanezumab monthly ranked in first place in both monthly headache day and monthly migraine day analyses. The calcitonin gene-related peptide monoclonal antibodies were consistently the best choices for headache/migraine days and headache-related quality of life. Topiramate was very unlikely to be the best choice for headache/migraine days and headache-related quality of life when compared to calcitonin gene-related peptide monoclonal antibodies or Botox. We found no trials of the commonly used drugs, such as propranolol or amitriptyline, to include in the analysis. The adverse events review included 40 randomised controlled trials with 25,891 participants; 3 additional drugs, amitriptyline, atogepant and rimegepant, were included. There were very few serious adverse events – none of which were linked to the use of these medications. Adverse events were common. Most people using some calcitonin gene-related peptide monoclonal antibodies reported injection site issues; and people using topiramate or amitriptyline had nervous system or gastrointestinal issues. The cost-effectiveness review identified 16 studies evaluating chronic migraine medications in adults. The newer, injected drugs are more costly than the oral preventatives, but they were cost-effective. Our economic model showed that topiramate was the least costly option and had the fewest quality-adjusted life-year gains, whereas eptinezumab 300 mg was more costly but generated the most quality-adjusted life-year gains. The cost-effectiveness acceptability frontier showed that topiramate was the most cost-effective medication if the decision maker is willing to pay up to £50,000 per quality-adjusted life-year. Our consensus workshop brought together people with chronic migraine and headache experts. Consensus was reached on the top three recommendations for future research on medications to prevent chronic migraine: (1) calcitonin gene-related peptide monoclonal antibodies and Botox versus calcitonin gene-related peptide monoclonal antibodies, (2) candesartan versus placebo and (3) flunarizine versus placebo. Limitations Topiramate was the only oral drug for which we were able to include data. We did not find sufficient quality evidence to support the use of other oral drugs. Conclusions We did not find evidence that the calcitonin gene-related peptide monoclonal antibodies are more clinically and cost-effective when compared to topiramate or Botox. We identified directions for future research these drugs might take. Study registration This study is registered as PROSPERO CRD42021265990, CRD42021265993 and CRD42021265995. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR132803) and is published in full in Health Technology Assessment; Vol. 28, No. 63. See the NIHR Funding and Awards website for further award information. Plain language summary What is the problem? Chronic migraine is a disabling condition that can destroy work and family life. Treatments include cheap tablets (e.g. amitriptyline, propranolol and topiramate), Botox and expensive new drugs (the calcitonin gene-related peptide monoclonal antibodies). It is not known which of these drugs is the best choice. What did we want to find out? We wanted to find out which of these drugs works best. We wanted to know if they reduced the number of headache/migraine days and improved headache-related quality of life, how many side effects people experienced, and if they provided good value for the National Health Service. How did we do this? We first looked for research comparing these drugs to placebo (fake) drugs, and to each other. We then worked out which provide best value for money. What did we find out? Calcitonin gene-related peptide monoclonal antibodies reduced headache/migraine days by 2.0–2.5 days per month; Botox reduced headache/migraine days per month by around 1.9; and topiramate reduced headache/migraine days by 1.1–1.5 days per month. Many people taking topiramate or amitriptyline have nervous system and/or stomach/bowel side effects. Some people using calcitonin gene-related peptide monoclonal antibodies reported side effects associated with injections. Some calcitonin gene-related peptide monoclonal antibodies and Botox provide worthwhile benefits on headache-related quality of life. We were not able to identify any studies of sufficient quality to assess the effectiveness of other oral drugs. The best value drug was topiramate which gave better health outcomes at a lower cost than the placebos. What does this mean? After sharing the results with a panel of people with chronic migraine and headache experts, we identified a need for new studies comparing commonly used cheap oral drugs with placebo, Botox and calcitonin gene-related peptide monoclonal antibodies. Scientific summary Background Chronic migraine is a profoundly disabling condition and affects 2–4% of the world’s adult population. It is defined as headaches on 15 days or more a month with features of migraine on at least 8 of those days. Since 2020, expensive calcitonin gene-related peptide (CGRP) monoclonal antibodies (MAbs) have become established as specific treatments for people with chronic migraine who have failed to improve with other medications. Little is known about the effectiveness of these drugs when compared with each other, or with other well-established, cheaper, oral drugs used to treat chronic migraine. Therefore, it is timely to compare the clinical effectiveness and cost-effectiveness of these medications to treat chronic migraine. We set out to address the following research question: What is the clinical effectiveness and cost-effectiveness of prophylactic drug treatments for people with chronic migraine? Objectives Our overall aim is to produce evidence needed for people with chronic migraines and their doctors to make more informed decisions about prophylactic medications for chronic migraine. Our objectives were: What is the comparative effectiveness of prophylactic drugs for chronic migraine? What are the comparative incidences of adverse events (AEs) of prophylactic drugs used for migraine? What is known about the cost-effectiveness of prophylactic drugs for chronic migraine? Which prophylactic drugs for the management of chronic migraine are the most cost-effective? Based on our findings, what should the research recommendations be? Methods Systematic reviews of trial evidence on: The clinical effectiveness of prophylactic medications for chronic migraine; analyses included headache days, migraine days and headache-related quality of life: migraine- specific quality of life (MSQ); headache impact test-6 (HIT-6). Only randomised controlled trials (RCTs) with at least 100 people per arm were included. We report the comparative effectiveness using a network meta-analysis (NMA) for these different outcomes to see which drug was the most ‘effective’. To identify the comparative incidence of AEs of prophylactic drugs used for chronic or episodic migraine. RCTs with at least 100 people per arm were included. The cost-effectiveness studies of prophylactic drugs used for treatment of chronic migraine. We developed an economic model comparing the cost-effectiveness of prophylactic drugs for chronic migraine for the adult population from a National Health Service (NHS) and personal social services (PSS) perspective. The base-case analysis used a 2-year time horizon, with a starting age of 30 years for the patient cohort. Health states in the model were based on effectiveness data [reduction in the mean difference (MD) in monthly headache days (MHDs)] from the NMA. Costs are in 2021–2 prices and utilities were estimated based on EuroQol-5 Dimensions, five-level version (EQ-5D-5L) scores from the CHESS trial using the Hernandez-Alava crosswalk algorithm. Cost-effectiveness was measured in terms of an incremental cost per quality-adjusted life-year (QALY) gained [Institute for Clinical and Economic Review (ICER)]. Probabilistic sensitivity analysis (PSA) was undertaken to account for uncertainty in model parameters. Uncertainty around the cost-effectiveness of the various medications showing which is the preferred strategy is presented using a cost-effectiveness acceptability frontier (CEAF). At the end of the project, we held a consensus workshop bringing together people with chronic migraine and clinicians and other health professionals who are experts in chronic migraine. We presented the findings from our reviews, NMA, the economic model and some potential recommendations. We then split into groups (mixed with health professionals and participants) and asked them to discuss our suggested research recommendations, identify any other recommendations, and rank these recommendations in terms of priority. We then had another breakaway session, where all participants with chronic migraine met and all health professionals met. Finally, everyone was bought back together to discuss their rankings as a wider group and to reach a consensus using anonymous polling. Results The clinical effectiveness review focused on prophylactic medications which might be used in the UK for the prevention of chronic migraine. We found 11 RCTs reported across 51 individual publications, involving 7352 adult participants with chronic migraine, which showed that all pharmacological treatments for all outcomes of interest were beneficial in preventing migraine when compared to placebo. There were no trials of sufficient quality of the commonly used drugs, such as amitriptyline, candesartan, flunarizine or propranolol. Overall, the CGRP MAbs reduced headache/migraine days by 2.0 to 2.5 days per month. The most effective medication in reducing MHDs was eptinezumab 300 mg which reduced MHDs by 2.46 [95% credible interval (CrI) 3.24 to −1.67] days. The most effective medication in reducing monthly migraine days (MMDs) was fremanezumab monthly which reduced MMDs by 2.76 (95% CrI −3.36 to −2.15) days. Botox (BTA) reduced MHDs by 1.87 (95% CrI −2.55 to −1.18) days per month and MMDs by 1.96 (95% CrI −2.69 to −1.24) days per month. Topiramate was the least effective, prescribable drug and only reduced headache/migraine days by less than 1.5 fewer headache/migraine days per month. The NMA results showed that eptinezumab 300 mg had the highest probability ranking to reduce MHDs and MMDs – Surface Under the Cumulative Ranking Area (SUCRA) was 0.88 and 0.77, respectively. The CGRP MAbs provided a worthwhile improvement on the HIT-6 measure of headache-related quality of life (eptinezumab 300 mg reducing the HIT-6 by a score of 3.22 points); BTA had a worthwhile effect on the HIT-6 measure, reducing the HIT-6 score by 2.10 points; and there was no convincing benefit of topiramate on the MSQ measure. Galcanezumab 120 mg provided the best improvement in quality of life for the preventative role dimension of migraine-specific quality of life (MSQ-PR) (MD 6.97, 95% CrI 3.79 to 10.24, SUCRA 0.88), but for two other dimensions of the MSQ, erenumab 140 mg was superior to other treatments: for migraine-specific quality of life-restrictive role (MSQ-RR) – MD: 7.28, 95% CrI: 3.05 to 11.65, SUCRA 0.75, and for migraine- specific quality of life-emotional function (MSQ-EF) – MD: 8.89, 95% CrI: 3.20 to 14.55, SUCRA 0.79. The results from the quality assessment using the revised Cochrane risk-of-bias (RoB 2) tool for RCTs found that approximately 46% of the included RCTs in this review had low RoB and 36% of the RCTs had some concerns of bias. The incidence of AEs and serious adverse events (SAEs) review used evidence from 40 RCTs reported across 67 articles, which investigated pharmacological interventions to manage chronic or episodic migraine. These trials included 25,891 participants and 3 additional drugs were included – amitriptyline, atogepant and rimegepant. There were very few SAEs – none of which were linked to the use of these drugs. Non-SAEs were common, and results suggested that all the pharmacological medications included in this review were found to be tolerable. There were differences in the incidence of AEs between the CGRP MAbs, with most people using fremanezumab and one in four people using galcanezumab reporting injection site issues. These issues were much less common in people using eptinezumab or erenumab. Most people using topiramate or amitriptyline had nervous system or gastrointestinal side effects; topiramate was also linked to a higher prevalence of psychiatric disorders; and AEs related to BTA were uncommon. The cost-effectiveness review identified nine peer-reviewed journal articles and seven published reports of chronic migraine prophylactic medications in the adult population. All articles were model-based evaluations, and none were trial-based economic evaluations. We found that although these newer drugs (BTA and CGRP MAbs) were more costly than the oral preventatives, they were however deemed cost-effective. Generally, the articles were classed as high quality when appraised by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting tool. We developed a Markov (state-transition) model to assess the cost-effectiveness of different pharmacological medications to treat or prevent chronic migraine in the adult population. Our base-case deterministic results showed when comparing each of the medications separately against placebo, topiramate dominated placebo (cheaper and more effective); and each of the other medications, when compared separately, were more expensive than placebo; however, they generated more QALYs than placebo. The best value medication when compared with placebo was BTA, with the cost per QALY around £25,000. When comparing all medications together, the deterministic results showed that topiramate was the least costly option and had slightly more QALY gains than placebo, whereas eptinezumab 300 mg was the more costly option but generated the most QALY gains. Most medications were eliminated due to dominance. The ICER between BTA and topiramate and the ICER between eptinezumab 300 mg and BTA were not within plausible cost-effectiveness thresholds. Probabilistic results were similar to deterministic results. The CEAF showed that when comparing all medications topiramate was the most cost-effective medication if the decision maker is willing to pay up to £50,000 per QALY. None of the CGRP MAbs represented good value for money in this comparative analysis. Extensive sensitivity analyses showed that when MHDs is used as an outcome measure, the results were generally in line with the base-case results. The main exception was when using MMDs as an outcome measure instead of MHDs, fremanezumab monthly generated more QALY gains than eptinezumab 300 mg; the ICERs between the plausible options, once any dominated options were removed, were not within plausible cost-effectiveness thresholds. Our consensus workshop brought together 8 participants with chronic migraine and 11 health professionals with expertise in chronic migraine to set research priorities for preventive drugs for chronic migraine. Each of the small groups found that the need for trials of cheaper, oral medications, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors (SNRIs) when compared with placebo were ranked highly; and for trials comparing the medications with each other, the CGRP MAbs and BTA separately or in combination with each other were ranked highly. The final (anonymised) rankings showed that the top three research priorities versus placebo were: (1) candesartan, (2) flunarizine and (3) melatonin; and for medications compared with each other were: (1) CGRP MAbs and BTA versus CGRP MAbs, (2) CGRP MAbs versus BTA and (3) a multi-arm trial of CGRPs MAbs receptor (erenumab) versus CGRP MAbs ligand (eptinezumab, fremanezumab and galcanezumab). In terms of priority, a consensus was established regarding the three most recommended medication comparisons for treating chronic migraine: (1) CGRP MAbs and BTA versus CGRP MAbs, (2) candesartan compared to placebo and (3) flunarizine in comparison to placebo. Discussion and conclusions Of the treatments included in the NMA, the CGRP MAbs overall were consistently the best choices for headache days, migraine days and headache-related quality of life. BTA was less likely than CGRP MAbs to be the best choice for headache days, migraine days and headache-related quality of life. Topiramate was very unlikely to be the best choice for headache days, migraine days and headache-related quality of life when compared to CGRP MAbs or BTA. The economic model found that topiramate was the best value drug if you are prepared to pay up to £50,000 per QALY. It is likely that CGRP MAbs are likely to be cost-effective in people who have failed treatment with BTA. At the workshop, general consensus was agreed on the top three choices of medication for chronic migraine. Topiramate was the only established oral drug for which we were able to include data. It is disappointing that we did not find a sufficient quality evidence base to support the use of drugs, such as amitriptyline, candesartan, flunarizine and propranolol that are recommended by National Institute for Health and Care Excellence (NICE) and/or Scottish Intercollegiate Guidelines Network (SIGN). Our consensus meeting identified the need for trials comparing candesartan and flunarizine with placebo as the top priorities for placebo-controlled trials. Only for topiramate can we make any observations for how this may compare with CGRP MAbs. The CGRP MAbs appear to be clinically superior, but even so topiramate, in spite of its high incidence of AEs, represents the best value for money. Within the current care pathway, it is unlikely that CGRP MAbs will be recommended ahead of topiramate without a very substantial reduction on price. What is perhaps a more critical decision point is whether BTA or CGRP MAbs might be preferred as the first choice after failure of oral medication. Our findings support continuing with the current care pathway since our CEAF found that only topiramate met an acceptable threshold. Data from our health economics review, however, do support the use of CGRP MAbs after failure of BTA for chronic migraine. Our consensus group identified the direct comparison of BTA and CGRP MAbs as a key research question. They also identified the question of whether these drug effects might be additive. The effect sizes, in terms of mean monthly migraine/headache days for each of these drugs, are at best modest, the largest being 2.76 days for fremanezumab monthly dose. As these drugs work through different pathways, it might be that more substantial effects are possible. Adding together the effects of BTA and a CGRP MAb, assuming no negative interaction, might have a mean effect size of 4–5 days that would be transformative for many people with chronic migraine. Our consensus group identified the comparative, and additive, effects of BTA and CGRP MAbs as high priority research questions. In conclusion, we have summarised the existing clinical and cost-effectiveness data on preventive drugs for chronic migraine and identified which directions future research on these drugs might take. We did not find convincing evidence that the CGRP MAbs are more clinically effective and cost-effective compared to topiramate or BTA. Study registration This study is registered as PROSPERO CRD42021265990, CRD42021265993 and CRD42021265995. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR132803) and is published in full in Health Technology Assessment; Vol. 28, No. 63. See the NIHR Funding and Awards website for further award information.
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