Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Percentage of patients who respond well is misleading.
- Sally Kerry (16 January 2001)
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Percentage of patients who respond well is not misleading
- Harald Schrader (24 January 2001)
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Migraine prophylaxis with better tolerability
- F H Degenring (7 February 2001)
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ACE-inhibitors and migraine
- C Canepari, M Riva (8 February 2001)
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LISINOPRIL AND OTHER ACE-INIBITHORS IN MIGRAINE
- CELIO LEVYMAN,MD,ScM (24 October 2003)
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Sally Kerry, Lecturer in Medical Statistics St. George's Hospital Medical School
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Dear Editor We agree with the conclusion of Schrader et al1 that their study shows that lisinopril has a prophylactic effect in migraine. However comparing treatment period with placebo, the effect on days with migraine and hours with headache is modest, about 20%. The authors then state that 'a reduction of at least 50% for days with migraine were seen in 30% of patients during the lisinopril treatment compared with the placebo period'. We believe that this statement gives a misleading impression of the effectiveness of the treatment. Firstly, it is not clear whether this was part of the initial analysis plan - it was not stated as such. In particular was the 50% cut- off point chosen prior to the analysis of the data or after? If the latter, then the choice of cut-off is data-dependent and hence biased. Secondly, in most trials some patients will appear to respond better than others. This may be due to true variability in effectiveness or random variability in the outcome variable. In a crossover trial with considerable natural variability in outcome from one time period to another, some patients may be observed to have large positive changes in outcome between time periods even in the absence of a treatment effect. At the same time, some patients may show large negative changes in outcome. To simply report the positive changes for active versus placebo in a crossover design is meaningless and gives the impression of greater treatment effect than there really is. In addition, we noted that in fact a very similar number of patients failed to complete the study as were reported to respond well (13/60 dropped out or failed to comply, of the 47 remaining 14 were reported to have responded well). We suggest that in abstracts, the emphasis should be on the results of primary analyses and that subgroup or post-hoc analyses are given less prominence. Sally Kerry
Janet Peacock
St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE 1. Schrader H, Stovner, LJ, Helde G, Sand T, Bovim G.Prophylactic treatment of migraine with angiotensin converting inhibitor (lisinopril): randomised ,placebo controlled, crossover study. BMJ 2001;322:1-5 |
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Harald Schrader, Professor of Neurology Norwegian University of Science and Technology, Department of Neurology, 7006 Trondheim, Norway
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Response to the letter of Sally Kerry, 16 January 2001. Dear Editor The “50 % cut-off point” mentioned in Kerry’s response [1] to our study on migraine-prophylaxis with lisinopril [2] refers to so-called responders, who according to a standard definition are patients who during active treatment have a reduction of 50 % or more in efficacy parameters. Several previous studies on migraine prophylaxis refer to this definition. We used, of course, this definition prior to the analysis of data and did thus not choose some cut-off point after seeing our results. It seemed necessary to us to report the results concerning number of “responders” in order to enable comparisons to what other authors have found. We disagree with Kerry and Peacock that one sentence in the abstract referring these results justify the notion that this analysis is given too much prominence. Unfortunately, the editors made the mistake to repeat most of this sentence in the abstract, an error which was not present in the editorial typescript seen by us. Hopefully, this has not contributed to what this criticism calls misleading impression. We agree with Kerry and Peacock that the great natural variability in attack frequency in some patients may lead to large differences in efficacy parameters even in the absence of a treatment effect. However, in the present study this variability seemed to be of minor importance since a similar number of responders (n=17) was seen when comparing the active drug treatment period with the run-in period. These 17 patients included all 14 patients who had a 50 % or more reduction of migraine days when comparing the active treatment period with the placebo period. Most importantly, however, only one of the fully evaluable patients (n = 47) and two of the patients who entered the intention to treat analysis (n = 55) had a 50% or more reduction of migraine days during the placebo period as compared to the active treatment period. Originally, we intended to report the positive changes for placebo versus active treatment, but omitted it because we already had reached the maximum length of our article. In view of the relevant response by Kerry and Peacock we recognize that we should have given these data in order to avoid any misinterpretation as to the efficacy of the treatment. Harald Schrader
Lars Jacob Stovner
Norwegian University of Science and Technology , Department of Neurology, 7006 Trondheim, Norway 1. Kelly S. Percentage of patients who respond well is misleading. BMJ, 16 January 2001. 2. Schrader H, Stovner LJ, Helde H, Sand T, Bovim G. Prophylactic treatment of migraine by an angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled crossover study. BMJ 2001; 322:19. |
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F H Degenring Medical Department
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Dear Sirs We may inform you that comparable results in efficacy but without any adverse reactions had been reached by a randomized double blind placebo- controlled study (33 verum vs. 27 placebo patients) with an extract of Petasites hybridus rhizoma (Butterbur root). The frequency of the migraine -attacks per month was significantly reduced (50%) compared to placebo (10%) after 12 weeks of therapy. The phytomedicament appeared to be even more effective in the subgroup of patients with a frequency higher than 3 attacks per month. The Petasistes-capsules are available in Switzerland as Petadolor and in Germany as Petadolex. Further details are presented in the publication of M. Grossmann and H. Schmidramsl: An extract of Petasites hybridus is effective in the prophylaxis of migraine. Internat. J. Clin. Pharm. & Ther. 38: 430-435 (2000). |
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C Canepari Ospedale Niguarda, Milano,Italy, M Riva
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After reading the article written by H. Schrader et al. “Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril):randomised, placebo controlled, crossover study” (5), some considerations have arisen. The use of ACE-inhibitors as prophylactics in headache treatment was first proposed by F. Sicuteri in 1981 (6). The “rationale” for this was the inhibition of dipeptidyl-carboxypeptidase, an enkephalin inactivating enzyme. This hypothesis was supported in 1986 by Baldi et al. (1) who found an increased plasma level of b-endorphynes in migraine sufferers after assumption of a single oral dose of captopril. In 1986 we wanted to try captopril in 42 migraine-hypertensive patients in an open study (30 treated with captopril and 12 with other classic antihypertensive drugs, excluding Ca2+ channel blockers, clonidine and â- blockers). The result was a stable normalisation of arterial blood- pressure but the symptom headache did not show any statistically significant difference between the two groups . Although more recent studies, Paterna et al -1992- (3), indicate the clinical utility of captopril in preventing migraine, ACE-inhibitors are still neither recommended nor used by headache-specialists. We suggest that the efficacy of lisinopril as well as other ACE-inhibitors should be proved by several investigations. C.Canepari, M. Riva
REFERENCES 1.Baldi E, Conti P, Conti R, Fanciullacci M, Michelacci S, Salmon S, Sicuteri F, Spillantini MG . Hypernociceptive syndromes and pharmacological nhibition of endogenous opioid degradation. Int J Clin Pharmacol Res 1986;6(3):193-7 2.Bender WI. ACE Inhibitors for Prophylaxis of Migraine Headaches. Headache 1995;35: 470-1. 3.Paterna S, di Pasquale P, Martino S, Arrostuto A, Ingurgio NC, Parrinello G, Gullotti D, Licata G. Captopril versus placebo nella prevenzione dell’emicrania senza aura. Studio in doppio cieco randomizzato. Clin. Ter. 1992 Dec.; 141(12): 475-81. 4.Riva M, Canepari C, Delzanno GB. Clinical experience with captopril in migraine-hypertensive patients. Eur Rev Med & Pharmacol 1986; 8: 183- 8. 5.Schrader H, Stovner LJ, Helde G, Sand T, Bovin G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ 2001; 322:19. 6.Sicuteri F. Enkephalinase inhibition relieves pain syndromes of central dysnociception (migraine and related headache). Cephalalgia 1981 Dec; 1(4):229-32. |
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CELIO LEVYMAN,MD,ScM, Private Office Neurology and Headache Clinic,Rua Jose Janarelli,199/22,Sao Paulo,SP,Brazil,01124-010
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LISINOPRIL AND OTHER ACE-INHIBITORS IN MIGRAINE The paper of Shrader et al is very interesting, but certain things must be recorded. In the 80’ Sicuteri proposed the use of captopril, based in encephalin studies. Federico Sicuteri is one of the grater names of the field of headache treatment.However,must of the drugs in use for prophylactic treatment of migraine are poor understood in regard of they mechanism of action.Sicuteri,Lance,Graham,Antonaci and other great names of the initial neurotransmitter basis of pathophysiology of migraine think most in a serotonin-basis model. Despite the Sicuteri results, other authors could not reproduce the reports of the Florence researchers. When we think in migraine as a receptor disease, and this is of particular useful way to explain triptan effects, we are lost to explain ACE- inhibitors drugs in treatment of migraine.Topiramate seems to work: but in witch way ?And I don't say nothing about propranolol and other beta- blockers... Although the well designed study, an ancient point must to be pointed: placebo works well than nothing, as all people in the field of pain treatment know: perhaps liberation of endorphins could explain this fact, but the migraine patient produces endorphins with more difficulty than normal ones. All of us, neurologists with special interest in headache and pain, want new drugs to the prophylaxis of the migraine – lisinopril could be one of these drugs, but the placebo effect could not be discharged, and also the pharmaceutical industry interests. We must pray to lisinopril or other drugs acting as ACE-inhibitors could be a good option; in the meantime, propranolol, amytriptiline, flunarizine and even topiramate are the chooses of the moment. Study pain treatment is not easy, and subjective factors could also play a role in these studies. Let us treat migraine patients in an individual way, and wait for must studies. Competing interests: None declared |
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