Viewpoint/Perspective
What efficacy measures are clinically relevant and should be used in Cochrane Reviews of acute migraine trials? A viewpoint
Cephalalgia 2015, Vol. 35(5) 457–459 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414545347 cep.sagepub.com
Peer Tfelt-Hansen Abstract Background: Cochrane Reviews are methodologically of high quality but the clinical relevance of analysed efficacy measures (EMs) should also be assessed. Methods: The clinical relevance of EMs used in one systematic Cochrane review of oral zolmitriptan for migraine headache was evaluated. Results: The following EMs were used: pain free at two hours (30%), headache relief at two hours (60%), sustained pain free for 24 hours (19%) and sustained headache relief for 24 hours (39%). These EMs were also used in four other Cochrane reviews of acute migraine treatment. Of these EMs sustained headache relief for 24 h is not judged clinically relevant. Conclusion: Pain free and sustained pain free are clinically relevant, but the responses are rather low, demonstrating that there is a need for improvement of acute drug treatment in migraine. Keywords Migraine, acute treatment, efficacy measures, triptans Date received: 7 June 2014; accepted: 21 June 2014
The Cochrane Collaboration states that ‘Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognised as the highest standard in evidence-based health care’ (http://www.cochrane.org/ cochrane-reviews). With such a declaration the Cochrane Reviews should be like Caesar’s wife, that is, not even suspected of wrongdoings. In the recent Cochrane review on zolmitriptan from 2014 it is stated (1): ‘‘In selecting the main outcome measures for this review we considered scientific rigor, availability of data, and patient preferences. Patients with acute migraine headaches have rated complete pain relief, no headache recurrence, rapid onset of pain relief, and no side effects as the four most important outcomes (2). In view of these patients’ preferences, and in line with the guidelines for controlled trials of drugs in migraine issued by the International Headache Society (IHS) (3), we considered the following main outcomes:
Primary outcomes Pain free at two hours, without the use of rescue medication. Reduction in headache pain (‘headache relief’) at two hours (pain reduced from moderate or severe to none or mild without the use of rescue medication).
Secondary outcomes Sustained pain-free during the 24 hours post-dose (pain free within two hours, with no use of rescue medication or recurrence of pain of any intensity within 24 hours).
Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital Glostrup, Denmark Corresponding author: Peer Tfelt-Hansen, Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital, Glostrup DK-2600, Denmark. Email: [email protected]
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Cephalalgia 35(5)
Table 1. Four efficacy outcomes used in a Cochrane Review of oral zolmitriptan (Bird et al., 2014). Results for zolmitriptan (Zolmi.) 2.5 mg and placebo (Plac.) are presented. Pain free at two hours (PF)
Headache relief at two hours (HR)
Sustained pain free for 24 hours (SPF)
Sustained headache relief for 24 hours (SHR)
Drugs
Zolmi.
Plac.
Zolmi.
Plac.
Zolmi.
Plac.
Zolmi.
Plac.
Absolute % NNT Therapeutic gain
30% 5 20%
10%
60% 3.2 31%
29%
19% 7.7 13%
6%
39% 4.1 24%
14%
NNT: numbers needed to treat.
Sustained headache relief during the 24 hours post-dose (headache relief at two hours with no use of rescue medication or a second dose of study medication, or recurrence of moderate or severe pain within 24 hours). Adverse events: participants with any adverse event during 24 hours post-dose; serious adverse events; adverse events leading to withdrawal.’’
For an overview of the results of the review, see Table 1, which illustrates a considerable variability in the apparent efficacy of oral zolmitriptan 2.5 mg as judged from the four efficacy measures (EMs). Apart from apparently demonstrating low or high efficacy, the more important question is the clinical relevance of these efficacy outcomes which also were used in a Cochrane Review of oral sumatriptan (4). The Drug Trial Subcommittee of the IHS has evaluated this problem and has published guidelines for drug trials in migraine in 1991 (5), 2000 (3) and in 2012 (6). In 1991 sustained pain free (SPF) was the suggested primary EM (5), and in 2000 and 2012 it was recommended as a secondary EM (3,6). Pain free (PF) was recommended as the primary EM in the guidelines from 2000 and 2012 (3,6). Headache relief (HR), for definition see above, is an invention of Glaxo for use in the sumatriptan trial programme (7). Despite some inherent shortcomings, see IHS Clinical Trial Subcommittee (3) for discussion, and the fact that patients want to be pain free (2), HR has been used extensively in triptan trials (8). HR has been recommended by IHS only as a secondary efficacy outcome ‘mainly to facilitate comparison of results in new randomized clinical trials (RCTs) with those
of previous trial programmes for the triptans’ (3,6). In the future HR will become even less relevant because it cannot be used in trials in which patients can treat in the mild phase of headache (9). Sustained headache response (SHR) was used in triptan trials probably from the late 1990s and was advocated by Goldstein et al. in 1999 (10) as a way to address recurrences. It is, however, in my and the IHS’ view (6) not a useful efficacy outcome. There is no requirement for pain freedom, which is what the patients want (2,11), and the problem with recurrence is addressed sufficiently with the SPF outcome. In addition, patients have never expressed satisfaction with this efficacy outcome. Consequently, SHR was not mentioned at all in the IHS guidelines from 2000 (3), and in the 2012 guidelines it is stated that ‘sustained response is not recommended as a secondary efficacy outcome measure’ (6). In conclusion: PF and SPF are clinically relevant efficacy measures and ‘the two endpoints together incorporate the main treatment attributes that determine patient satisfaction (i.e. rapid and sustained freedom from pain)’ (12), but both have relatively low absolute response rates and therapeutic gains with oral zolmitriptan 2.5 mg, see Table 1, demonstrating that there is a need for improvement of acute drug treatment in migraine. HR can be used as a secondary efficacy outcome mainly in order to allow a comparison with results in previous trials using this outcome (3,6). In contrast, SHR, lacking clinical relevance (see above), should not be used as a secondary efficacy outcome in systematic reviews. The impetus for the use of SHR is probably that SPF is very low for all triptans and SHR looks much nicer in the promotion of these drugs.
Clinical implications . Pain free (PF) and sustained pain free (SPF) should be used when judging an acute migraine trial. . Sustained pain relief is not clinically relevant. . PF and SPF responses are low, demonstrating the need for improvement of acute migraine therapy.
Tfelt-Hansen
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Bird S, Derry S and Moore RA. Zolmitriptan for acute migraine attacks in adults. Cochrane Database Syst Rev 2014; 5: CD008616. 2. Lipton RB and Stewart WF. Acute migraine therapy: Do doctors understand what patients want from therapy? Headache 1999; 39(Suppl 2): S20–S26. 3. Tfelt-Hansen P, Block G, Dahlo¨f C, et al. Guidelines for controlled trials of drugs in migraine. Second edition. Cephalalgia 2000; 20: 765–786. 4. Derry CJ, Derry S and Moore RA. Sumatriptan (oral route of administration) for acute migraine in adults. Cochrane Database Syst Rev 2012; 2: CD008615. 5. Guidelines for controlled trials of drugs in migraine. International Headache Society Committee on Clinical Trials in Migraine. Cephalalgia 1991; 11: 1–12.
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6. Tfelt-Hansen P, Pascual J, Ramadan N, et al. Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators. Cephalalgia 2012; 32: 6–38. 7. Pilgrim AJ. Methodology of clinical trials of sumatriptan in migraine and cluster headache. Eur Neurol 1991; 31: 295–299. 8. Ferrari MD, Goadsby PJ, Roon KI, et al. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: Detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633–658. 9. Gendolla A. Early treatment in migraine: How strong is the evidence? Cephalalgia 2008; 28(Suppl 2): 28–36. 10. Goldstein DJ, Offen WW and Moster MB. Efficacy definitions or migraine studies. Cephalalgia 1999; 19: 248–249. 11. Davies GM, Santanello N and Lipton RB. Determinants of patient satisfaction with migraine therapy. Cephalalgia 2000; 20: 554–560. 12. Silberstein SD, Newman LC, Marmura MJ, et al. Efficacy endpoints in migraine clinical trials: The importance of assessing freedom from pain. Curr Med Res Opin 2013; 29: 861–867.
What efficacy measures are clinically relevant and should be used in Cochrane Reviews of acute migraine trials? A viewpoint
Cephalalgia 2015, Vol. 35(5) 457–459 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414545347 cep.sagepub.com
Peer Tfelt-Hansen Abstract Background: Cochrane Reviews are methodologically of high quality but the clinical relevance of analysed efficacy measures (EMs) should also be assessed. Methods: The clinical relevance of EMs used in one systematic Cochrane review of oral zolmitriptan for migraine headache was evaluated. Results: The following EMs were used: pain free at two hours (30%), headache relief at two hours (60%), sustained pain free for 24 hours (19%) and sustained headache relief for 24 hours (39%). These EMs were also used in four other Cochrane reviews of acute migraine treatment. Of these EMs sustained headache relief for 24 h is not judged clinically relevant. Conclusion: Pain free and sustained pain free are clinically relevant, but the responses are rather low, demonstrating that there is a need for improvement of acute drug treatment in migraine. Keywords Migraine, acute treatment, efficacy measures, triptans Date received: 7 June 2014; accepted: 21 June 2014
The Cochrane Collaboration states that ‘Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognised as the highest standard in evidence-based health care’ (http://www.cochrane.org/ cochrane-reviews). With such a declaration the Cochrane Reviews should be like Caesar’s wife, that is, not even suspected of wrongdoings. In the recent Cochrane review on zolmitriptan from 2014 it is stated (1): ‘‘In selecting the main outcome measures for this review we considered scientific rigor, availability of data, and patient preferences. Patients with acute migraine headaches have rated complete pain relief, no headache recurrence, rapid onset of pain relief, and no side effects as the four most important outcomes (2). In view of these patients’ preferences, and in line with the guidelines for controlled trials of drugs in migraine issued by the International Headache Society (IHS) (3), we considered the following main outcomes:
Primary outcomes Pain free at two hours, without the use of rescue medication. Reduction in headache pain (‘headache relief’) at two hours (pain reduced from moderate or severe to none or mild without the use of rescue medication).
Secondary outcomes Sustained pain-free during the 24 hours post-dose (pain free within two hours, with no use of rescue medication or recurrence of pain of any intensity within 24 hours).
Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital Glostrup, Denmark Corresponding author: Peer Tfelt-Hansen, Danish Headache Center, University of Copenhagen, Department of Neurology, Glostrup Hospital, Glostrup DK-2600, Denmark. Email: [email protected]
458
Cephalalgia 35(5)
Table 1. Four efficacy outcomes used in a Cochrane Review of oral zolmitriptan (Bird et al., 2014). Results for zolmitriptan (Zolmi.) 2.5 mg and placebo (Plac.) are presented. Pain free at two hours (PF)
Headache relief at two hours (HR)
Sustained pain free for 24 hours (SPF)
Sustained headache relief for 24 hours (SHR)
Drugs
Zolmi.
Plac.
Zolmi.
Plac.
Zolmi.
Plac.
Zolmi.
Plac.
Absolute % NNT Therapeutic gain
30% 5 20%
10%
60% 3.2 31%
29%
19% 7.7 13%
6%
39% 4.1 24%
14%
NNT: numbers needed to treat.
Sustained headache relief during the 24 hours post-dose (headache relief at two hours with no use of rescue medication or a second dose of study medication, or recurrence of moderate or severe pain within 24 hours). Adverse events: participants with any adverse event during 24 hours post-dose; serious adverse events; adverse events leading to withdrawal.’’
For an overview of the results of the review, see Table 1, which illustrates a considerable variability in the apparent efficacy of oral zolmitriptan 2.5 mg as judged from the four efficacy measures (EMs). Apart from apparently demonstrating low or high efficacy, the more important question is the clinical relevance of these efficacy outcomes which also were used in a Cochrane Review of oral sumatriptan (4). The Drug Trial Subcommittee of the IHS has evaluated this problem and has published guidelines for drug trials in migraine in 1991 (5), 2000 (3) and in 2012 (6). In 1991 sustained pain free (SPF) was the suggested primary EM (5), and in 2000 and 2012 it was recommended as a secondary EM (3,6). Pain free (PF) was recommended as the primary EM in the guidelines from 2000 and 2012 (3,6). Headache relief (HR), for definition see above, is an invention of Glaxo for use in the sumatriptan trial programme (7). Despite some inherent shortcomings, see IHS Clinical Trial Subcommittee (3) for discussion, and the fact that patients want to be pain free (2), HR has been used extensively in triptan trials (8). HR has been recommended by IHS only as a secondary efficacy outcome ‘mainly to facilitate comparison of results in new randomized clinical trials (RCTs) with those
of previous trial programmes for the triptans’ (3,6). In the future HR will become even less relevant because it cannot be used in trials in which patients can treat in the mild phase of headache (9). Sustained headache response (SHR) was used in triptan trials probably from the late 1990s and was advocated by Goldstein et al. in 1999 (10) as a way to address recurrences. It is, however, in my and the IHS’ view (6) not a useful efficacy outcome. There is no requirement for pain freedom, which is what the patients want (2,11), and the problem with recurrence is addressed sufficiently with the SPF outcome. In addition, patients have never expressed satisfaction with this efficacy outcome. Consequently, SHR was not mentioned at all in the IHS guidelines from 2000 (3), and in the 2012 guidelines it is stated that ‘sustained response is not recommended as a secondary efficacy outcome measure’ (6). In conclusion: PF and SPF are clinically relevant efficacy measures and ‘the two endpoints together incorporate the main treatment attributes that determine patient satisfaction (i.e. rapid and sustained freedom from pain)’ (12), but both have relatively low absolute response rates and therapeutic gains with oral zolmitriptan 2.5 mg, see Table 1, demonstrating that there is a need for improvement of acute drug treatment in migraine. HR can be used as a secondary efficacy outcome mainly in order to allow a comparison with results in previous trials using this outcome (3,6). In contrast, SHR, lacking clinical relevance (see above), should not be used as a secondary efficacy outcome in systematic reviews. The impetus for the use of SHR is probably that SPF is very low for all triptans and SHR looks much nicer in the promotion of these drugs.
Clinical implications . Pain free (PF) and sustained pain free (SPF) should be used when judging an acute migraine trial. . Sustained pain relief is not clinically relevant. . PF and SPF responses are low, demonstrating the need for improvement of acute migraine therapy.
Tfelt-Hansen
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Bird S, Derry S and Moore RA. Zolmitriptan for acute migraine attacks in adults. Cochrane Database Syst Rev 2014; 5: CD008616. 2. Lipton RB and Stewart WF. Acute migraine therapy: Do doctors understand what patients want from therapy? Headache 1999; 39(Suppl 2): S20–S26. 3. Tfelt-Hansen P, Block G, Dahlo¨f C, et al. Guidelines for controlled trials of drugs in migraine. Second edition. Cephalalgia 2000; 20: 765–786. 4. Derry CJ, Derry S and Moore RA. Sumatriptan (oral route of administration) for acute migraine in adults. Cochrane Database Syst Rev 2012; 2: CD008615. 5. Guidelines for controlled trials of drugs in migraine. International Headache Society Committee on Clinical Trials in Migraine. Cephalalgia 1991; 11: 1–12.
459
6. Tfelt-Hansen P, Pascual J, Ramadan N, et al. Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators. Cephalalgia 2012; 32: 6–38. 7. Pilgrim AJ. Methodology of clinical trials of sumatriptan in migraine and cluster headache. Eur Neurol 1991; 31: 295–299. 8. Ferrari MD, Goadsby PJ, Roon KI, et al. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: Detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633–658. 9. Gendolla A. Early treatment in migraine: How strong is the evidence? Cephalalgia 2008; 28(Suppl 2): 28–36. 10. Goldstein DJ, Offen WW and Moster MB. Efficacy definitions or migraine studies. Cephalalgia 1999; 19: 248–249. 11. Davies GM, Santanello N and Lipton RB. Determinants of patient satisfaction with migraine therapy. Cephalalgia 2000; 20: 554–560. 12. Silberstein SD, Newman LC, Marmura MJ, et al. Efficacy endpoints in migraine clinical trials: The importance of assessing freedom from pain. Curr Med Res Opin 2013; 29: 861–867.
