Results from a blind and a non-blind randomised trial run in parallel: experience from the Estonian Postmenopausal Hormone Therapy (EPHT) Trial
Tóm tắt
The Estonian Postmenopausal Hormone Therapy (EPHT) Trial assigned 4170 potential participants prior to recruitment to blind or non-blind hormone therapy (HT), with placebo or non-treatment the respective alternatives. Before having to decide on participation, women were told whether they had been randomised to the blind or non-blind trial. Eligible women who were still willing to join the trial were recruited. After recruitment participants in the non-blind trial (N = 1001) received open-label HT or no treatment, participants in the blind trial (N = 777) remained blinded until the end of the trial. The aim of this paper is to analyse the effect of blinding on internal and external validity of trial outcomes. Effect of blinding was calculated as the hazard ratio of selected chronic diseases, total mortality and all outcomes. For analysing the effect of blinding on external validity, the hazard ratios from women recruited to the placebo arm and to the non-treatment arm were compared with those not recruited; for analysing the effect of blinding on internal validity, the hazard ratios from the blind trial were compared with those from the non-blind trial. The women recruited to the placebo arm had less cerebrovascular disease events (HR 0.43; 95% CI: 0.26-0.71) and all outcomes combined (HR 0.76; 95% CI: 0.63-0.91) than those who were not recruited. Among women recruited or not recruited to the non-treatment arm, no differences were observed for any of the outcomes studied. Among women recruited to the trial, the risk for coronary heart disease events (HR 0.77; 95% CI: 0.64-0.93), cerebrovascular disease events (HR 0.66; 95%CI: 0.47-0.92), and all outcomes combined (HR 0.82; 95% CI: 0.72-0.94) was smaller among participants in the blind trial than in the non-blind trial. There was no difference between the blind and the non-blind trial for total cancer (HR 0.95; 95% CI: 0.64-1.42), bone fractures (0.93; 95% CI: 0.74-1.16), and total mortality (HR 1.03; 95% CI: 0.53-1.98). The results from blind and non-blind trials may differ, even if the target population is the same. Blinding may influence both internal and external validity. The effect of blinding may vary for different outcome events. [
ISRCTN35338757
]
Tài liệu tham khảo
Godwin M, Ruhland L, Casson I, MacDonald S, Delva D, Birthwhistle R, Lam M, Seguin R: Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity. BMC Med Res Methodol. 2003, 3: 28-10.1186/1471-2288-3-28.
Altman DG: Randomisation. BMJ. 1991, 302: 1481-1482. 10.1136/bmj.302.6791.1481.
Altman DG, Bland JM: Treatment allocation in controlled trials: why randomise?. BMJ. 1999, 318: 1209-
Day SJ, Altman DG: Blinding in clinical trials and other studies. BMJ. 2000, 321: 504-10.1136/bmj.321.7259.504.
The CONSORT Statement. (accessed April 14, 2011), [http://www.consort-statement.org/consort-statement/]
Rothwell PM: External validity of randomised controlled trials: "to whom do the results of this trial apply?". Lancet. 2005, 365: 82-93. 10.1016/S0140-6736(04)17670-8.
Moher D, Jadad AR, Nichol G, Penman M, Tugwell P, Walsh S: Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Controlled Clin Trials. 1995, 16: 62-73. 10.1016/0197-2456(94)00031-W.
Section VI: Preparing and maintaining systematic reviews. Cochrane Collaboration handbook. Edited by: Oxman AD. 1994, Oxford: Cochrane Collaboration
Dekkers OM, von Elm E, Algra A, Romijn JA, Vanderbroucke JP: How to assess the external validity of therapeutic trials: a conceptual approach. Int J Epidemiol. 2010, 39: 89-94. 10.1093/ije/dyp174.
Rothwell PM: Commentary: external validity of results of randomised trials: disentangling a complex concept. Int J Epidemiol. 2010, 39: 94-96. 10.1093/ije/dyp305.
Veerus P, Hovi SL, Fischer K, Rahu M, Hakama M, Hemminki E: Results from the Estonian Postmenopausal Hormone Therapy (EPHT) Trial [ISRCTN35338757]. Maturitas. 2006, 55: 162-173. 10.1016/j.maturitas.2006.01.012.
Veerus P, Fischer K, Hovi SL, Hakama M, Rahu M, Hemminki E: Postmenopausal hormone therapy increases use of health services: experience from the Estonian Postmenopausal Hormone Therapy Trial [ISRCTN35338757]. Am J Obstet Gynecol. 2006, 195: 62-71. 10.1016/j.ajog.2005.12.037.
Veerus P, Fischer K, Hovi SL, Karro H, Rahu M, Hemminki E: Symptom reporting and quality of life in the Estonian Postmenopausal Hormone Therapy Trial. BMC Women's Health. 2008, 8: 5-10.1186/1472-6874-8-5.
Hemminki E, Hovi SL, Veerus P, Sevon T, Tuimala R, Rahu M, Hakama M: Blinding decreased recruitment in a prevention trial of postmenopausal hormone therapy. J Clin Epidemiol. 2004, 57: 1237-1243. 10.1016/j.jclinepi.2004.04.009.
Vorobjov S, Hovi SL, Veerus P, Pisarev H, Rahu M, Hemminki E: Treatment adherence in the Estonian Postmenopausal Hormone Therapy (EPHT) Trial [ISRCTN35338757]. Maturitas. 2005, 52: 286-295. 10.1016/j.maturitas.2005.05.001.
Veerus P, Fischer K, Hovi SL, Karro H, Hemminki E: Does hormone replacement therapy affect the use of prescription medicines in postmenopausal women: experience from the Estonian Postmenopausal Hormone Therapy Trial [ISRCTN35338757]. BJOG. 2007, 114: 548-554. 10.1111/j.1471-0528.2007.01292.x.
Veerus Piret: The Impact of Postmenopausal Hormone Therapy on Health and Use of Health Services: Experience from the Estonian Postmenopausal Hormone Therapy (EPHT) trial. 2007, Helsinki: Gummerus
World Health Organization: International Statistical Classification of Diseases and Related Health Problems. Tenth Revision. 1992, Geneva: WHO
Estonian Health Insurance Fund. (accessed April 14, 2011), [http://www.haigekassa.ee/eng/]
Lang K, Mägi M, Aareleid T: Study of completeness of registration at the Estonian cancer registry. Eur J Cancer Prev. 2003, 12: 153-156. 10.1097/00008469-200304000-00009.
The R Project for Statistical Computing. (accessed April 14, 2011), [http://www.r-project.org/]
Halpern SD: Evaluating preference effects in partially unblinded, randomised clinical trials. J Clin Epidemiol. 2003, 56: 109-115. 10.1016/S0895-4356(02)00598-X.
Flemming DC: Prescribing placebos: value in the placebo response. BMJ. 2008, 337: 1252-10.1136/bmj.a1252.
Shapiro S: Risks of estrogen plus progestin therapy: a sensitivity analysis of findings in the Women's Health Initiative randomised controlled trial. Climacteric. 2003, 6: 302-310.
Garbe E, Suissa S: Hormone replacement therapy and acute coronary outcomes: methodological issues between randomised and observational studies. Hum Reprod. 2004, 19: 8-13. 10.1093/humrep/deh022.
Schulz KF, Chalmers I, Hayes R, Altman DG: Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995, 273: 408-412. 10.1001/jama.1995.03520290060030.
Pildal J, Hróbjartsson A, Jørgensen KJ, Hilden J, Altman DG, Gøtzsche PC: Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials. Int J Epidemiol. 2007, 36: 847-857. 10.1093/ije/dym087.
Black N: Why we need observational studies to evaluate the effectiveness of health care. BMJ. 1996, 312: 1215-1218. 10.1136/bmj.312.7040.1215.
Silverman WA, Altman DG: Patients' preferences and randomised trials. Lancet. 1996, 347: 171-174. 10.1016/S0140-6736(96)90347-5.
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