Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
No role for anticholinergics??
- Andrew E Brooke (22 April 2003)
-
Overactive bladder: anticholinergics have statistically and clinically significant benefit
- Aravinthan Coomarasamy, Dukaydah van der Berg, Neelima Deshpande, John R. Pogmore (24 April 2003)
-
Cover headline is misleading
- David R Grimshaw, Simon R Jackson, Consultant Urogynaecologist,John Radcliffe Hospital, OX3 9DU (24 April 2003)
-
Behavioural interventions in the management of the overactive bladder.
- Tim Lane, Tim Lane, Christian Brown and Mark Emberton (25 April 2003)
-
What did this study add to the field, except opinion?
- Wendy P. Battisti (25 April 2003)
-
DEFINING THE ROLE OF ANTICHOLINERGIC THERAPY
- Dudley Robinson, Linda Cardozo, John Bidmead,James Balmforth, Matthew Parsons, Kate Anders and Andrea Dixon (2 May 2003)
-
The authors reply
- Peter Herbison, Jean Hay-Smith, Gaye Ellis, and Kate Moore (29 May 2003)
-
Clinical versus Patient Outcomes: Whose outcome has greater value?
- Karin S. Coyne, Con J. Kelleher; Guy's and St Thomas' NHS Trust, London, UK (4 November 2003)
|
|
|||
|
Andrew E Brooke, GP Gloucester. GL1 5JJ
Send response to journal:
|
It seems to be a fact of medical publishing that different publications may put their own emphasis of points arising from a new piece of published research. I find it hard to reconcile the front cover statement " Overactive bladder: no role for anticholinergics " with the contents of the paper itself. The box stating " what this study adds " concludes that "anticholinergics produce significant improvements in overactive bladder symptoms compared with placebo." Improvement in symptoms in overactive bladder syndrome is, in my experience, largely what patients are looking for. Competing interests: None declared |
|||
|
|
|||
|
Aravinthan Coomarasamy, Specialist Registrar in Obstetrics and Gynaecology and Honorary Lecturer in Epidemiology Education Resource Centre, Birmingham Women's Hospital, Edgbaston, UK B15 2TG, Dukaydah van der Berg, Neelima Deshpande, John R. Pogmore
Send response to journal:
|
Editor – We commend Herbison et al for their comprehensive review of anticholinergic drugs for treatment of overactive bladder.[1] However, we were concerned that the authors’ assertion that “the benefits are, however, of limited clinical significance” and the BMJ’s clinical bottomline on the front cover “Overactive bladder: no role for anticholinergics” (BMJ, 19 April 2003) were both incorrect and irresponsible – incorrect, as these conclusions bear no relation to the actual results of the review, and irresponsible, as these unnecessarily pessimistic conclusions can cause harm by denying an effective treatment to many. We, therefore, infer appropriate conclusions from the results of this review below. Although relative measures of effectiveness (like relative risk, relative risk reduction, or odds ratio) are useful for assessing the biological strength of effect, absolute measures of effectiveness (like absolute risk reduction or number needed to treat (NNT)) are generally needed for assessing the clinical significance of an intervention.[2] This is because when even a small relative risk reduction (or increase) is applied to a common condition (with high baseline risk), the absolute benefit can be substantial. One example of this would be antihypertensive treatment in hypertensive patients to prevent cardiovascular events – although the relative risk reduction was modest at 25%, in high-risk groups, the absolute benefit was found to be substantial with an absolute risk reduction of 12.5% and an NNT of just 8.[3] Now considering the outcome of “cure or improvement”, probably the most clinically relevant primary outcome in Herbison et al’s study,[1] the NNT† is 17 [1/(0.15x0.41)], where the relative risk increase is 41%[1] and the baseline risk of overactive bladder is taken as 15%.[4] Of course, when the baseline risk of bladder overactivity is greater than 15% (as it would be in a secondary or tertiary clinic setting, for example) the NNT would be even lower. For instance, if the baseline risk of bladder overactivity was 50%, then the NNT would be just 5 [1/(0.5x0.41)], which would be consistent with an effectiveness that would be considered extremely “clinically significant”. Compare these NNTs with NNTs for some interventions that have been commonly accepted as clinically significant and therefore worthy of introduction or continuation of use in clinical practice: folate therapy to pregnant women to prevent neural tube defects – NNT=139; streptokinase infusion after acute myocardial infarction to prevent death – NNT=19, and daily aspirin after acute myocardial infarction to prevent death – NNT=24. We thus maintain that the evidence for the anticholinergics is statistically and clinically significant, although it should be noted that clinical significance is ultimately a matter of judgement that individual patients and clinicians would need to make taking into account not just the clinical effectiveness of a drug, but also issues such as the importance of the outcome(s) being prevented, side-effects, safety profile and the cost. † NNT = 1/absolute risk reduction or increase = 1/ [baseline risk x relative risk reduction or increase] Aravinthan Coomarasamy, Specialist Registrar in Obstetrics and Gynaecology, and Honorary Lecturer in Public Health and Epidemiology Education Resource Centre, Birmingham Women’s Hospital, Birmingham B15 2TG. Dukaydah van der Berg, General Practice Registrar
Neelima Deshpande, Consultant Urogynaecologist and Obstetrician
John R Pogmore, Consultant Urogynaecologist and gynaecologist
1. Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 2003;326:841-4. 2. Glasziou PP, Irwig LM. An evidence based approach to individualising treatment. BMJ 1995;311:1356-9. 3. Therapy and Applying the Results - Example Numbers Needed to Treat. Lacchetti C, Guyatt G, Devereaux PJ. In: Guyatt G, Rennie D, eds. Users' Guide to the Medical Literature - A Manual for Evidence-based Practice. Chicago: JAMA & Archives Journals, 2002. 4. Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU.Int. 2001;87:760-6. Competing interests: None declared |
|||
|
|
|||
|
David R Grimshaw, General Practitioner Langford Medical Practice, 9 Nightingale Place, Bicester, Oxon, OX26 6XX, Simon R Jackson, Consultant Urogynaecologist,John Radcliffe Hospital, OX3 9DU
Send response to journal:
|
Editor - We read with a degree of surprise the front cover headline in a recent BMJ "Overactive bladder: no role for anticholinergics". Our clinical experience is that some patients with this condition clearly benefit from this class of drugs. On reading the paper (1) from which this headline was derived, a systematic review of randomised controlled trials looking at effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder, it emerges that these drugs cause a small but significant improvement in symptons of overactive bladder. This appears to be a very consistent finding amongst the assorted trials. The authors note that most people experienced a large improvement, but this was true for the placebo groups as well as for the treated groups. One can reasonably argue that in a condition with a large treatment placebo effect, an intervention which is no better than placebo may still have a potentially useful therapeutic role in the absence of being unable to prescribe "placebo". Even more useful still, therefore, is a treatment which is consistently better than placebo in such a condition. We feel, therefore, that it was extremely misleading to put this headline on the front cover of your journal. It flies in the face of the evidence base and also clinical reality. Having inappropriately written off this class of drugs we would be interested to learn how you would manage a women with this condition given the relative lack of effective alternatives. A subject for the next "10 minute consultation" perhaps. David R Grimshaw Competing interests: None declared |
|||
|
|
|||
|
Tim Lane, Clinical Lecturer Queen Mary Westfield School Medicine. London. EC1, Tim Lane, Christian Brown and Mark Emberton
Send response to journal:
|
Dear Sir, We read with interest the article by Herbison et al[1]. Of particular interest was their plea for a more pragmatic approach to evaluating patients with an overactive bladder syndrome. A strong criticism of the work performed to date relates to the use of placebo as a control. They argue for the use of a behavioural approach such as bladder retraining as a comparator. This seems logical given that behavioural approaches are offered to most individuals with lower urinary tract symptoms (many of which will have over active bladders) as a first line of therapy. It is possible that behavioural approaches may prove more effective for longer and lack the harms associated with pharmacotherapy. We would not stop at bladder drill as one of the potential interventions [2]. It could be that fluid scheduling, caffeine restriction, pelvic floor exercises and the optimised management of co- morbid conditions could all have a place in the management of the overactive bladder syndrome [3,4]. In this respect it is interesting that these interventions are routinely offered by continence advisors and urology nurse specialists but not by physicians [5]. What is also interesting is that with a few exceptions, physicians have not subjected these interventions to rigorous study [6]. If they prove to be as effective as many believe them to be, the knowledge will transform the management of all patients with lower urinary tract symptoms and could potentially impact on 60% of the men and women over the age of 50. Mr Tim Lane FRCS BSc (Hons)
Mr Christian Brown MRCS BSc (Hons)
Mr Mark Emberton MD FRCS
REFERENCES 1. Herbison P, Hay-Smith J, Ellis G and Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ (2003) 841-844 2. Weinberger M, Goodman B, Carnes M. Long-term efficacy of non-surgical urinary incontinence treatment in elderly women. Journal of Gerontology (1999) 54(3): 117-21 3. Iqbal P, Casteden C. Management of urinary incontinence in the elderly. Gerontology (1997) 43(3): 151-7 4. Creighton S, Stanton S. Caffeine: does it affect your bladder?. BJU(1990) 66(6):613-4 5. Brown CT, van der Meulen J, Mundy AR, Emberton M. Lifestyle and behavioural interventions for men on watchful waiting with uncomplicated lower urinary tract symptoms: A national multidisciplinary survey. BJU Int. (In press) 6. Sobel D. Rethinking Medicine: Improving health outcomes with cost- effective psychosocial interventions. Psychosomatic Medicine (1995) 57:234 -244 7. Kadow C, Fennely, Abrams P. Prostatectomy or conservative management of benign prostatic hypertrophy. BJU (1988) 61:432-434 Competing interests: None declared |
|||
|
|
|||
|
Wendy P. Battisti, Assoc. Director, Clinical Research Publications Merck & Co., Inc. 19486
Send response to journal:
|
After reading this article, I didn’t feel the analysis conducted by these authors resolved any of the “uncertainty (that) still exists as to their (anticholinergics) effectiveness, which ones are best, and which is the optimal route of administration” as proposed in the introduction. In fact, I felt the rationale for this study was not adequately described or supported by the background information provided in the introduction. Thus, I was left wondering exactly what information the authors hoped to reveal conducting this type of study. My sense was that rather than being interested in sound scientific analysis, the authors had a preconceived notion about anticholinergics (e.g., that they were not particularly useful, often cause side effects, and are increasing in number and use without their effectiveness having been established either overall) and were determined to prove their opinion, no matter what the outcome. In fact, they offer many unsupported statements that appear as conclusions, but are only opinion disguised as a study result. This error first appears with the second to last statement in the conclusion of the abstract. This statement (regarding the outcome “being of questionable clinical significance”) is opinion and there is no information provided in this analysis that supports this statement. This type of statement should never appear under the heading “conclusion”. In fact, the last statement of the abstract is also misplaced; determining the number of long-term studies was not a specified objective of their analysis. Since there is very little information provided on the length of the studies used in the analysis, one wonders why the authors would want to highlight study length in the abstract. I also wondered what is the point of the leading, potentially inflammatory statement: “Many studies showed that trials sponsored by drug companies have more favourable outcomes than those with independent funding”? The paragraph continues by then mentioning only the number of trials that were supported by a pharmaceutical company, rather than what may be different about trial design, size, population, power, or outcome measures, to account for the purported discrepancy. Where was the data to support this “conclusion”? Again, the analysis was not designed to make that kind of comparison. Thus, this type of statement is misleading and more in keeping with tabloid journalism. The statement “the benefits are of limited clinical significance” is startling, particularly since it is presented as a highlight in the “What this study adds” section. This statement is merely opinion. The article presents no data that support this. In fact, one could easily argue just the opposite, based on these authors’ own results and description of the problems associated with overactive bladder. I am still asking myself what did this research add to the field? And exactly what was the authors rationale - or agenda? Competing interests: I am employed by a pharmaceutical company. I have no competing interest in terms of drug therapies for the the treatment of overactive bladder. |
|||
|
|
|||
|
Dudley Robinson, Sub-Specialty Urogynaecology Dept of Urogynaecology, Kings College Hospital, London. SE5 9RS, Linda Cardozo, John Bidmead,James Balmforth, Matthew Parsons, Kate Anders and Andrea Dixon
Send response to journal:
|
Dear Editor, The large meta-analysis, reviewing the role of anticholinergic therapy, reported by Herbison (1) and colleagues is a valuable overview of the many studies that have been performed assessing the management of patients complaining of irritative urinary symptoms suggestive of an overactive bladder. Whilst we acknowledge the findings of the study we feel that the conclusions may be misleading. The results show that those subjects taking anticholinergics were significantly more likely to be subjectively improved, had fewer episodes of incontinence and also had reduced frequency of micturition. Whilst overall this only equated to one less episode of incontinence and one less void over a 24-hour period this can be clinically relevant, particularly in terms of quality of life evaluation. When considering diurnal frequency, which is defined as 8 or more voids per day, a change from 12 to 11 voids per day would represent a reduction of 25% of the excess voids. The same would not be true for urinary incontinence episodes which most women would like to reduce to zero. In our experience of managing women with overactive bladder this represents a significant clinical improvement; frequency/nocturia, urgency and urge incontinence being the most bothersome reported lower urinary tract symptoms (2). Furthermore these subjective findings are supported in the meta-analysis by objective improvement in urodynamic parameters of maximum cystometric capacity and volume at first detrusor contraction. There remains considerable debate regarding what constitutes ‘cure’ for women with lower urinary tract dysfunction (3). A questionnaire study of patients and clinicians has shown that subjective improvement in urinary symptoms and improvement in quality of life are considered to be the most important measures of outcome and this is reflected in the fact that all new studies in the management of overactive bladder incorporate quality of life evaluation. Thus, whilst objective parameters are clearly important in the research setting subjective improvement is what is clinically important to patients and doctors. Anticholinergic therapy and bladder retraining have previously been compared in women with detrusor overactivity (4) although, as the authors suggest there remains a need for a pragmatic comparison of the new anticholinergic drugs and bladder retraining since this would provide valuable information regarding their synergistic role in everyday clinical practice. Meta-analysis is valuable as a tool for evidence based medicine although we should be wary that, by looking at the evidence too closely, we ignore a therapeutic effect that leads to subjective clinical improvement in bothersome lower urinary tract symptoms. References 1.Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 2003; 326: 841-4. 2.Robinson D, Anders K, Cardozo L, Bidmead J, Dixon A, Balmforth J, Rufford J, Hinoul P. What women want – Their interpretation of the concept of cure. Neurourol Urodyn 2002 21(4): 429-430. 3.Tincello DG, Alfirevic Z. Important clinical outcomes in urogynaecology: views of patients, nurses and medical staff. Int Urogynaecol J 2002; 13:96 -98. 4.Jarvis GJ. A controlled trial of bladder drill and drug therapy in the management of detrusor instability. Br J Urol 1981; 53 (6): 565-6. Competing interests: None declared |
|||
|
|
|||
|
Peter Herbison, Statistictian Dunedin School of Medicine, Jean Hay-Smith, Gaye Ellis, and Kate Moore
Send response to journal:
|
We agree with Brooke, and Grimshaw and Jackson in that we would have much preferred to have a question mark after the front cover statement about our trial. We simply concluded that there should be questions asked about whether the small difference we found were beneficial to patients. The title was chosen for the front cover by the editorial staff of the Journal, not by the authors. There is no perfect measure for summarising effectiveness. Both relative and absolute measures have their problems. While the calculations carried out by Coomarasamy et al of numbers needed to treat are correct, we think the results should be interpreted with caution. They base their calculations on subjective cure and improvement. If a patient changes from having to void 12 time a day to voiding 11 times a day then that is improvement, but it is questionable whether the patient would be satisfied. As Robinson et al say, much more research needs to be done to determine what is a satisfactory amount of change. We think people may be prepared to put up with more (e.g. side effects, having to take drugs) if the adverse event that may be prevented is death or a neural tube defect, than if it is one extra void or leakage episode every second day. Grimshaw and Jackson, say that they cannot prescribe a placebo, but much of the so called placebo effect may be regression to the mean. There are other things that they can do, as suggested by Lane et al and Robinson et al such as lifestyle advice and bladder retraining. These have not been rigorously compared with drug treatment. Battisti could hardly have been further from the mark when she claims that we must have had a preconceived notion about anticholinergics before we started the review. We did the review because it was an important one for the Cochrane Incontinence Group, and we had raised some money to help with systematic reviews. We are a statistician, a physiotherapist and a research assistant who all had very little knowledge at all about anticholinergics at the start of the review process and a clinician who used them regularly and finds them generally helpful. It is surprising that Battisti questions our comments on long term outcomes. Anticholinergics are unlikely to be curative so will only work if taken. The outcome at the end of the trial period, which was given in the table on the web, is likely to be when the treatment effect is at its maximum. In order to interpret results of systematic reviews it is important to understand potential biases. It has been shown many times than company sponsored studies are more favourable to drugs than independent studies. We do not comment on the reasons for this. We do not say that the drug company funded trials in this review had different results than the others. We appreciate the opportunity to expand the discussion about these drugs. Competing interests: We are the authors of the article |
|||
|
|
|||
|
Karin S. Coyne, Senior Research Scientist MEDTAP International, Bethesda, MD 20814, USA, Con J. Kelleher; Guy's and St Thomas' NHS Trust, London, UK
Send response to journal:
|
Patient reported outcomes such as symptom assessment, health-related quality of life (HRQL), and patient perceived clinical benefit, are clinically-relevant outcomes that should not be overlooked – particularly in symptom-defined conditions. By definition, overactive bladder is a symptom-defined condition characterized by urinary urgency, with or without urge incontinence, and usually with urinary frequency and nocturia (1). While Herbison et al.’s meta-analysis of anticholingeric drugs in the treatment of overactive bladder is methodologically sound, the authors focus only on clinical outcomes (micturition diaries and side effects) which are not necessarily the most pertinent outcomes to patients with overactive bladder. In many respects, the outcomes studied are not those which would be suggestive of clinically meaningful benefit to patients and, as such, the conclusions drawn cannot be made on the basis of this meta-analysis. As noted by Herbison et al., a reduction of 1 incontinence episode or micturition per day may not appear to be clinically significant. However, when patient perceived improvement was considered as a primary outcome, the effects of treatment were significantly greater than noted in the placebo group (RR = 1.41; 95% CI: 1.25 to 1.54; p < 0.0001). Patients with overactive bladder do perceive improvement with treatment, however, this outcome has not been well captured which is evident in Herbison et al.’s review. Of the 32 reviewed articles, only 16 studies (50%) reported results involving patient-reported outcomes. The most frequent patient- reported outcome was perceived treatment benefit (n= 9); only one study reported detailed HRQL findings (2). For symptom-defined conditions, patient-reported outcomes not only provide added value, but may actually be the more efficacious outcome and certainly the outcome the patient desires. Patrick et al (3) noted significant HRQL improvements in the Incontinence –Quality of Life (I-QOL) questionnaire with a 25% reduction in incontinence. Tomera et al (4) noted significant HRQL improvements and reduced symptom burden in the Overactive Bladder questionnaire (OAB-q) with a reduction of 1 incontinence episode per day. While such reductions may not appear clinically relevant, these reductions can and do improve patient HRQL and reduce symptom burden. Although micturition diaries capture clinical information and provide an “objective” clinical outcome, such diaries do not capture how patients are affected by OAB or how bothersome their symptoms may be. In contrast, patient-reported outcomes quantify the patient’s perceived impact of disease and treatment. Thus, before discounting the “clinical” benefit of anticholingerics on OAB, it is imperative to systematically examine the “patient” benefit of anticholingerics on OAB. Herbison et al. have presented favorable evidence regarding patient perceived treatment benefits, however to establish the value of patient outcomes, additional research is needed in this area using scientifically validated patient reported outcomes. Herbison’s research highlights the necessity of selecting the most appropriate outcome measures for clinical research. Meta-analyses such as these should address all outcomes reported, rather than only the clinically objective outcomes, to evaluate whether a drug therapy confers benefit. 1 Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wien A. The standardization of terminology of lower urinary tract function: Report from the standardization sub- committee of the International Continence Society. Neurourol Urodyn 2002;21:167–178. 2 Davila GW, Sanders S, for the Transdermal Oxybutynin Study Group. Transdermal oxybutynin: a multi-center, prospective, randomized, double- blind, placebo-controlled study in adults with urge urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2001;12(suppl 3):S43. 3 Patrick DL, Martin ML, Bushnell DM, Yalcin I Wagner TH, Buesching DP. Quality of life of women with urinary incontinence: Further development of the incontinence quality of life instrument (I-QOL). Urology 1999; 53: 71-76. 4 Tomera K, Coyne K, Matza L, Corey R. How responsive is the Overactive Bladder questionnaire (OAB-q) to changes in urgency, frequency, and incontinence? Value in Health 2002; 5(3); 278-279. Competing interests: KC is a consultant to pharmaceutical companies; CK received lecture fees and support for travel to meetings from Pfizer, Yamanouuchi, and Novartis. |
|||