Abstract
Objective
The objective of this article is to evaluate, in first attack eletriptan headache and pain-free nonresponders, the efficacy of treating a second and third attack with the same dose of eletriptan 40 mg (ELE-40).
Methods
Data were pooled from four randomized, double-blind, placebo-controlled, multiple attack studies of eletriptan in the treatment of migraine. The first-attack eletriptan headache (HNR) and pain-free (PFNR) nonresponder samples consisted of patients who did not achieve headache or pain-free responses at two hours, or sustained headache or pain-free responses at 24 hours. The efficacy of the same dose of eletriptan (vs placebo; PBO) in treating the second and third attacks was evaluated using a logistic regression model.
Results
Among Attack 1 eletriptan HNRs, treatment with ELE-40 (vs PBO) was associated with significantly higher two-hour headache response and pain-free rates, respectively, on both Attack 2 (48.8% vs 20.2%; 17.0% vs 3.9%; p < 0.0001 for both comparisons) and Attack 3 (37.4% vs 15.5%; 18.8% vs 3.2%; p < 0.0001 for both comparisons). Significantly higher sustained headache response and pain-free rates at 24 hours were also observed on both Attack 2 and Attack 3.
Conclusions
The results of this pooled analysis suggest that patients who have HNR or PFNR to an initial dose of eletriptan may respond when a second and third attack is treated with the same dose.
Introduction
Migraine is a chronic, recurrent, and frequently disabling disorder that affects 18% of women and 5% of men (1). The efficacy of oral triptans for the acute treatment of migraine has been established based on multiple randomized, double-blind, placebo-controlled trials (2,3). The results of meta-analyses indicate that approximately 35%–40% of patients do not achieve a headache response at two hours on the first triptan-treated attack (2,3).
Clinicians have several potential options for treating patients who do not respond on the first attack to treatment with a triptan. These options include: (1) continuing treatment with the same drug at the same dose for a second attack prior to making a therapeutic class change; (2) continuing treatment with the same drug, but: (a) shifting the time of dosing earlier, when headache pain is mild (unless this is already being performed by the patient); (b) increasing the dose of triptan; or (c) switching to an alternative formulation of the same triptan (if available); (3) switching to an alternative triptan; or (4) combination therapy: adding a second or third medication to the triptan (e.g. a nonsteroidal anti-inflammatory drug (NSAID) or neuroleptic).
Randomized, double-blind, placebo-controlled trials are designed to establish the efficacy of individual drugs, but are less well suited for providing evidence-based answers to many of the patient presentations that confront clinicians on a daily basis. Thus, we are unaware of studies that have evaluated, using a randomized, prospective design, the comparative effectiveness of various strategies for treating the population of patients who do not achieve a headache or pain-free response on the first attack. Typically, studies of unresponsive patients involve switching patients from triptan A to triptan B rather than using a randomized, parallel-group design to provide a head-to-head comparison of two or more therapeutic options.
The results of several meta-analyses indicate that eletriptan 40 mg is one of the most effective acute treatments for migraine (2,3). A recently published study reported a post-hoc analysis of the effect of dose escalation in this nonresponder population (4). Patients who had failed to respond to the 40 mg dose of eletriptan on three consecutive migraine attacks achieved headache response rates at two hours on the next three attacks that ranged from 42.5% to 60% when the dose of eletriptan was increased to 80 mg (vs 7% to 31% on placebo; p < 0.05 for all comparisons). These data indicate that dose escalation may be an effective treatment strategy in approximately 50% of individuals, even if they are nonresponders to three consecutive attacks at a lower dose.
The aim of this post-hoc analysis of first-attack eletriptan nonresponders was to determine the efficacy of treating a second (and third) attack with the same dose of eletriptan, prior to using alternative treatment strategies (i.e. dose escalation, combination therapy, or switching).
Methods
Data for the current analysis were pooled from four randomized, double-blind, placebo-controlled, multiple-attack studies of eletriptan in the treatment of migraine (5–8). The pooled studies include all multiple-attack studies of similar design that permitted analysis of treatment response to the same (40 mg) dose of eletriptan. All four studies were primarily conducted in headache centers, and had similar study entry criteria and study designs, which are described in detail in the primary publications. Briefly, eligible patients were men and women ≥18 years of age who experienced migraine with or without aura, with a typical headache frequency of at least one attack every six weeks. Patients were excluded if they reported frequent nonmigrainous headache, atypical migraine that had not previously responded to therapy, migraine with prolonged aura by the 1988 International Classification of Headache Disorders (ICHD), first edition, familial hemiplegic migraine, or basilar migraine by the 1988 ICHD-1, basilar-type migraine in the 2004 ICHD-2, and termed migraine with brain stem aura in the 2013 ICHD-3. Informed consent was obtained from all patients, and independent ethics committees in the appropriate countries approved the study prior to implementation.
Headache pain was rated by the patient on a four-point scale as 0 = none, 1 = mild pain, 2 = moderate pain, and 3 = severe pain. Headache response (the primary a priori endpoint in all four trials) was defined as improvement in headache intensity (on this four-point global scale), from a pre-treatment level of moderate or severe to a two-hour post-dose intensity of none (pain free) or mild in the three attacks treated with active drug. Pain-free response was also evaluated at 2 hours post-dose, and was defined as an intensity of “0” (no pain). Sustained headache response and pain-free response at 24 hours were also evaluated. The current pooled analysis included the 40 mg dose of eletriptan (ELE-40) and placebo (PBO), but not active comparator drugs or other doses of eletriptan that were used in several of the studies.
Analysis sample
Four separate eletriptan nonresponder subgroups were identified based on failure to meet one of the following four outcomes: (1) headache nonresponse at two hours (HNR); (2) pain-free nonresponse at two hours (PFNR); (3) sustained headache nonresponse at 24 hours (sust-HNR); and (4) sustained pain-free nonresponse at 24 hours (sust-PFNR). For each of the four subgroups, we report treatment response on Attacks 2 and 3 after treatment with the same 40 mg dose of eletriptan used to treat Attack 1. Attack 3 was analyzed regardless of treatment response on Attack 2.
The efficacy of eletriptan vs placebo was evaluated using a logistic regression model for each attack separately. The model included terms for treatment, study number, and baseline headache severity for each attack. All statistical tests of significance were performed at the 5% level of significance, and were two-sided tests unless otherwise specified. Analyses were not adjusted for multiplicity.
Results
Baseline Demographic and Clinical Characteristics by First Attack Responder Status (ITT sample).
ITT: intent to treat sample, consisting of patients who were randomized and received treatment.
Responder and non-responder subgroups in Table 1 are based on first attack 2 hours headache response (HNR).
For the total four-study combined sample, headache response at two hours on the first treated attack was significantly higher for ELE-40 vs PBO (65.5% vs 28.7%; p < 0.0001); pain free at two hours was significantly higher for ELE-40 vs PBO (31.0% vs 6.5%; p < 0.0001); sustained headache response at 24 hours was significantly higher for ELE-40 vs PBO (49.4% vs 16.4%; p < 0.0001); and sustained pain free at 24 hours was significantly higher for ELE-40 vs PBO (24.3% vs 5.1%; p < 0.0001).
Subjects Available for Analysis of the Second and Third Attack, n (%).
Number of subject who treated all three attacks (sample sizes vary for Attack #2 and #3 due to small differences in patient availability).
In each of the four Attack 1 nonresponder subgroups (HNR, PFNR, sust-HNR, sust-PFNR), treatment with ELE-40 was associated with a significantly superior efficacy outcome compared with placebo (on both Attack 2 and Attack 3) on each of the respective nonresponder criteria at two hours (HNR and PFNR) and at 24 hours (sust-HNR and sust-PFNR; Figure 1—left panel; p < 0.0001 for all comparisons). For example, in the HNR subgroup that did not achieve headache response at two hours on the first attack, treatment with ELE-40 resulted in significantly higher headache response rates compared with placebo on Attack 2 (48.8% vs 20.2%; p < 0.0001), and on Attack 3 (37.4% vs 15.5% (p < 0.0001). In the PFNR subgroup that did not achieve a pain-free response at two hours on the first attack, treatment with ELE-40 resulted in significantly higher pain-free rates compared with placebo on Attack 2 (17.0% vs 3.9%; p < 0.0001), and on Attack 3 (18.8% vs 3.2% (p < 0.0001). Sample size in second attack: headache response analysis (ELE, n = 170; PBO, n = 193); pain‐free analysis (ELE, n = 341; PBO, n = 254); sustained headache response analysis (ELE, n = 235; PBO, n = 227); sustained pain‐free analysis (ELE, n = 362; PBO, n = 258). Sample size in third attack: headache response analysis (ELE, n = 170; PBO, n = 193); pain‐free analysis (ELE, n = 345; PBO, n = 252); sustained headache response analysis (ELE, n = 241; PBO, n = 224); sustained pain‐free analysis (ELE, n = 368; PBO, n = 256).
Similarly, In the sust-HNR subgroup that did not have sustained headache response at 24 hours on the first attack, treatment with ELE-40 resulted in significantly higher sustained headache response for ELE-40 vs PBO on both Attack 2 and Attack 3 (Figure 1—right panel; p < 0.0001). Similarly, In the sust-PFNR subgroup that did not have sustained pain-free response at 24 hours on the first attack, treatment with ELE-40 resulted in significantly higher sustained pain-free response for ELE-40 vs PBO on both Attack 2 and Attack 3 (Figure 1—right panel; p < 0.0001).
Discussion
The results of this pooled analysis found that a substantial minority of migraine patients who are headache nonresponders at two hours (HNR) to the 40 mg dose of eletriptan on Attack 1 can still achieve a headache response at two hours on Attack 2 (49%) or Attack 3 (37%). This suggests that it may be a useful therapeutic option to treat a second attack with the same ELE-40 prior to choosing other treatment strategies, such as dose escalation, augmentation with a second agent (e.g. an NSAID or a neuroleptic), or switching to a different triptan. It should be noted that the proportion of patients in the eletriptan nonresponder subgroup who do achieve a headache response on a second attack is approximately 20% lower than is typically observed in a typical patient sample that is not selected for being nonresponders; two-hour pain-free and sustained headache response and sustained pain-free rates at 24 hours are similarly lower. It should also be noted that the two-hour headache response and pain-free rates observed in Attack 3 were lower than the rates observed in Attack 2. Unfortunately, we don’t have data available on subsequent attacks, which would help us to determine whether the lower response rate was attributable to fluctuation in treatment response, or whether it was an actual trend.
Treating eletriptan nonresponders with the same dose should typically be coupled with a recommendation that patients take their dose as early as possible after the onset of headache. An independent meta-analysis of placebo-controlled early treatment trials (vide Appendix E, in Helfand and Peterson (9)) found early treatment with ELE-40 to be associated with significantly higher two-hour pain-free (68%) and sustained pain-free (56%) rates.
As noted previously, increasing the dose of eletriptan from 40 mg to 80 mg has recently been reported to convert nonresponders to responders in up to 60% of patients (4). These results are not directly comparable to the results of the current analysis, since the dose escalation analysis was limited to a subgroup of patients who met a more stringent (three-attack) definition of nonresponse. Nonetheless, the somewhat higher response rates, despite the more stringent criteria for nonresponse, suggest that dose escalation (from 40 mg to 80 mg) may be a more effective treatment strategy. However, the decision to choose a dose escalation strategy or add another drug must also take into account medication tolerability by the individual patient.
In switch studies, eletriptan was found to be efficacious in patients who have not had a satisfactory response to either sumatriptan (7) or rizatriptan (tablets or melt formulation (10)). The reason for within-class differences in treatment response rate among triptans is uncertain, especially since receptor pharmacology and pharmacokinetics are relatively similar for triptans as a class.
For eletriptan, we are unaware of previous published data that report on the comparative efficacy, in nonresponders, of either an augmentations strategy (adding an NSAID or neuroleptic) or a switch strategy. A series of studies (11) have found that nonresponse to initial treatment with a triptan, most commonly sumatriptan, does not predict non-response to treatment with alternative triptan therapies. The results of the current analysis are consistent with this finding.
The most notable limitation of the current study is the post-hoc nature of the analysis, and the lack of adjustment for multiplicity. Randomized, prospective studies are needed to compare the efficacy of various treatment strategies for managing patients who are nonresponders to initial triptan therapy. An example of this type of trial is the large (N = 2876) National Institute of Mental Health (NIMH)-funded collaborative study “Sequenced Treatment Alternatives to Relieve Depression” (STAR*D; 12) that evaluated next-step treatment strategies in patients diagnosed with major depressive disorder who had inadequate response to their first prescribed antidepressant.
In conclusion, the results of this pooled analysis suggest that patients who do not respond to an initial dose of eletriptan may respond when a second and third attack is treated with the same dose. Evidence from previous analyses suggests that earlier dosing may increase the likelihood of response. More research is needed to determine the best “next step” treatment algorithm for migraine patients who do not respond to initial triptan therapy.
Clinical implications
The results of this pooled analysis suggest that patients who do not respond to an initial dose of eletriptan may respond when a second and third attack is treated with the same dose. These findings provide evidence to support a strategy in which eletriptan is used to treat three separate migraine attacks before the decision is made to switch to a different triptan, or use a dose escalation or augmentation approach.
Footnotes
Funding
This work was supported by Pfizer Inc.
Conflicts of interest
M. Almas and E. Ramos are full-time employees of Pfizer Inc.
Dr Tepper has served as a speaker, consultant, or scientific advisory board member for Allergan Inc; Autonomic Technologies Inc; GlaxoSmithKline; Helsinn Group; MAP Pharmaceuticals Inc; Merck & Co. Inc; Nautilus Neurosciences Inc; NuPathe Inc; and Zogenix Inc; and has received research support from Autonomic Technologies Inc; Bristol-Myers Squibb; Depomed Inc; GlaxoSmithKline; MAP Pharmaceuticals Inc; Merck & Co. Inc; NuPathe Inc; and Zogenix Inc. Dr Tepper has stock options from Autonomic Technologies Inc.
Dr Landy has no conflicts to declare.
E. Schweizer is the owner of Paladin Consulting Group Inc, which was a paid consultant to Pfizer Inc in connection with the development of this manuscript; and owns stock in Pfizer Inc and Novartis.