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We read with interest the editorial from Drs Maddern, Middleton and
Grant,1 being in large part a critical appraisal of our recently published
randomised trial of Tension-free Vaginal Tape (TVT).2 We wholly endorse
the view expressed by the authors that realistic funding for surgical
trials is crucial to their meaningful outcome, and that ‘top up’ or
contingency funding should be available so that trials do not remain
underpowered. Although this is one of the largest surgical trials in this
area, recruitment was indeed a significant problem within the time and
resources available. Anecdotally, collaborating surgeons reported
increasing difficulty in recruiting to the trial as patients became aware
of the new procedure and specifically requested TVT rather than random
allocation; although the trial was conducted in the NHS, the TVT procedure
was available outside the trial in most centres. Had additional funding
been made available, extension of the recruitment period, or increasing
the number of centres involved could have been considered. Further
analysis of the data from this trial showed a tendency for lower cure
rates for both procedures in centres contributing smaller numbers of
patients to the trial.3 Clearly the involvement of a larger number of
less experienced surgeons may have had a substantial effect on the cure
rates and complications.
We accept that our failure to recruit up to the calculated sample size in
this trial has an inevitable adverse effect on the power of its
conclusions. Indeed we emphasised this in our publication and in
subsequent commentary.2, 3 It must be recognised however that statistical
power is a rather fickle concept. Our own trial sought to recruit 394
patients, on the assumption of 90% cure from colposuspension,4 and that a
10% difference in cure would be clinically important. The trial only
achieved recruitment of 344 patients, and given that the success of
colposuspension actually found was lower that that expected from the
literature, the study had only 50% power to detect a 10% difference or 80%
power to detect a 15% difference between the procedures under review.2
The ongoing MRC study of open and laparoscopic colposuspension, which uses
similar outcome measures to our own trial, seeks to recruit 290 patients
on the assumption of 80% cure from colposuspension and that a 15%
difference in cure is clinically important.5 Surely this would suggest
that our own protocol assumptions were not unreasonable at the time they
were made.
Maddern and colleagues express concern at the biases inherent in our study
favouring TVT, based on our failure to test assumptions in the analysis,
and our handling of missing data. We accept this criticism, and recognise
that had we explored the range of possible scenarios e.g. that all missing
data from in one arm represented treatment failure and from the other arm
treatment success, our conclusions may have been different.
We
acknowledge that, in respect of our primary outcome, a more correct
interpretation may be that TVT may be better, worse, or the same as
colposuspension in this study; indeed the broad confidence intervals for
treatment difference which we published are indicative of this
uncertainty. Their titular conclusion of the editorial, however, that the
‘benefits of TVT remain unproven’ is in itself questionable.
As the
authors point out, women treated with TVT had shorter operating times,
reduced hospital stays, had less adverse impact on quality of life
surrounding their surgery, and returned to work and normal activities more
rapidly. Whilst the trade-offs that patients make in their decisions
regarding surgical treatment are difficult to quantify, it is clear that
more and more are choosing the less invasive approach,6 and that secondary
trial outcomes may be of primary significance to patients.7
Most will
happily trade-off the lack of long-term cure data for the benefit of rapid
recovery.
Whilst the broad definition of ‘intention to treat’ is clear, its full
application is only possible when complete outcome data are available for
all randomised subjects.8 The handling of post-randomisation withdrawals
is undoubtedly crucial in the interpretation of cure in surgical trials.3,
9 Within our trial, of those patients who underwent surgery, a similar
proportion in each arm attended for review at 6 months (TVT 92%,
colposuspension 90%). In most surgical studies the assumption is made
that those failing to return for follow up or with incomplete data have
comparable success rates to those with complete data, and they are
disregarded. As we had no evidence as to the nature of this group, non-
attenders were considered as treatment failures in the analysis, to
produce a conservative estimate of treatment effect.
The largest number of post-randomisation withdrawals in our trial occurred
before surgery. In our initial presentation10 and submission of the trial
for publication, we had undertaken what we, perhaps naively, described as
a ‘modified intention to treat analysis’, which included only those
patients undergoing surgery. The reasons for withdrawal from a trial are
unlikely to be random and the possibility of bias cannot be excluded; our
main concern however was to avoid the criticism of bias favouring the new
intervention, since more patients withdrew from the colposuspension arm
than the TVT arm. The advice from the editors and reviewers of our
manuscript was that all patients randomised must be included in the
analysis. It is therefore something of a frustration to us that Maddern
and colleagues now raise this particular criticism under an editorial
banner.
1. Maddern G, Middleton P, Grant A. Urinary stress incontinence.
British Medical Journal 2002;325:789-790.
2. Ward KL, Hilton P. Prospective multicentre randomised trial of tension-
free vaginal tape and colposuspension as primary treatment for stress
incontinence. British Medical Journal 2002;325:67-70.
3. Hilton P. Trials of surgery for stress incontinence - thoughts on the
'Humpty Dumpty principle'. British Journal of Obstetrics & Gynaecology
2002;109:1081-1088.
4. Jarvis GJ. Surgery for genuine stress incontinence. British Journal of
Obstetrics & Gynaecology 1994;101(5):371-374.
5. The MRC COLPO Trial - ISRCTN14969683. In: Register of Current
Controlled Trials; http://www.controlled-trials.com; accessed 19.10.2002.
7. Tincello DG, Alfirevic Z. Important clinical outcomes in urogynecology:
Views of patients, nurses and medical staff. International Urogynecology
Journal & Pelvic Floor Dysfunction 2002;13(2):96-98.
8. Hollis S, Campbell F. What is meant by intention to treat analysis?
Survey of published randomised controlled trials. British Medical Journal
1999;319:670-674.
9. Fergusson D, Aaron S, Guyatt G, Hebert P. Post-randomisation
exclusions: the intention to treat principle and excluding patients from
analysis. British Medical Journal 2002;325:652-654.
10. Ward K, Hilton P, Browning J. A randomised trial of colposuspension
and tension-free vaginal tape (TVT) for primary genuine stress
incontinence (abstract). Neurourology and Urodynamics 2000;19(4):386-388.
Competing interests:
As declared in our previous publication (BMJ 2002;325:67-70)
Competing interests:
No competing interests
01 November 2002
Paul Hilton
Consultant Gynaecologist
Karen L Ward
Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP
Pleasing some of the people none of the time
We read with interest the editorial from Drs Maddern, Middleton and
Grant,1 being in large part a critical appraisal of our recently published
randomised trial of Tension-free Vaginal Tape (TVT).2 We wholly endorse
the view expressed by the authors that realistic funding for surgical
trials is crucial to their meaningful outcome, and that ‘top up’ or
contingency funding should be available so that trials do not remain
underpowered. Although this is one of the largest surgical trials in this
area, recruitment was indeed a significant problem within the time and
resources available. Anecdotally, collaborating surgeons reported
increasing difficulty in recruiting to the trial as patients became aware
of the new procedure and specifically requested TVT rather than random
allocation; although the trial was conducted in the NHS, the TVT procedure
was available outside the trial in most centres. Had additional funding
been made available, extension of the recruitment period, or increasing
the number of centres involved could have been considered. Further
analysis of the data from this trial showed a tendency for lower cure
rates for both procedures in centres contributing smaller numbers of
patients to the trial.3 Clearly the involvement of a larger number of
less experienced surgeons may have had a substantial effect on the cure
rates and complications.
We accept that our failure to recruit up to the calculated sample size in
this trial has an inevitable adverse effect on the power of its
conclusions. Indeed we emphasised this in our publication and in
subsequent commentary.2, 3 It must be recognised however that statistical
power is a rather fickle concept. Our own trial sought to recruit 394
patients, on the assumption of 90% cure from colposuspension,4 and that a
10% difference in cure would be clinically important. The trial only
achieved recruitment of 344 patients, and given that the success of
colposuspension actually found was lower that that expected from the
literature, the study had only 50% power to detect a 10% difference or 80%
power to detect a 15% difference between the procedures under review.2
The ongoing MRC study of open and laparoscopic colposuspension, which uses
similar outcome measures to our own trial, seeks to recruit 290 patients
on the assumption of 80% cure from colposuspension and that a 15%
difference in cure is clinically important.5 Surely this would suggest
that our own protocol assumptions were not unreasonable at the time they
were made.
Maddern and colleagues express concern at the biases inherent in our study
favouring TVT, based on our failure to test assumptions in the analysis,
and our handling of missing data. We accept this criticism, and recognise
that had we explored the range of possible scenarios e.g. that all missing
data from in one arm represented treatment failure and from the other arm
treatment success, our conclusions may have been different.
We
acknowledge that, in respect of our primary outcome, a more correct
interpretation may be that TVT may be better, worse, or the same as
colposuspension in this study; indeed the broad confidence intervals for
treatment difference which we published are indicative of this
uncertainty. Their titular conclusion of the editorial, however, that the
‘benefits of TVT remain unproven’ is in itself questionable.
As the
authors point out, women treated with TVT had shorter operating times,
reduced hospital stays, had less adverse impact on quality of life
surrounding their surgery, and returned to work and normal activities more
rapidly. Whilst the trade-offs that patients make in their decisions
regarding surgical treatment are difficult to quantify, it is clear that
more and more are choosing the less invasive approach,6 and that secondary
trial outcomes may be of primary significance to patients.7
Most will
happily trade-off the lack of long-term cure data for the benefit of rapid
recovery.
Whilst the broad definition of ‘intention to treat’ is clear, its full
application is only possible when complete outcome data are available for
all randomised subjects.8 The handling of post-randomisation withdrawals
is undoubtedly crucial in the interpretation of cure in surgical trials.3,
9 Within our trial, of those patients who underwent surgery, a similar
proportion in each arm attended for review at 6 months (TVT 92%,
colposuspension 90%). In most surgical studies the assumption is made
that those failing to return for follow up or with incomplete data have
comparable success rates to those with complete data, and they are
disregarded. As we had no evidence as to the nature of this group, non-
attenders were considered as treatment failures in the analysis, to
produce a conservative estimate of treatment effect.
The largest number of post-randomisation withdrawals in our trial occurred
before surgery. In our initial presentation10 and submission of the trial
for publication, we had undertaken what we, perhaps naively, described as
a ‘modified intention to treat analysis’, which included only those
patients undergoing surgery. The reasons for withdrawal from a trial are
unlikely to be random and the possibility of bias cannot be excluded; our
main concern however was to avoid the criticism of bias favouring the new
intervention, since more patients withdrew from the colposuspension arm
than the TVT arm. The advice from the editors and reviewers of our
manuscript was that all patients randomised must be included in the
analysis. It is therefore something of a frustration to us that Maddern
and colleagues now raise this particular criticism under an editorial
banner.
1. Maddern G, Middleton P, Grant A. Urinary stress incontinence.
British Medical Journal 2002;325:789-790.
2. Ward KL, Hilton P. Prospective multicentre randomised trial of tension-
free vaginal tape and colposuspension as primary treatment for stress
incontinence. British Medical Journal 2002;325:67-70.
3. Hilton P. Trials of surgery for stress incontinence - thoughts on the
'Humpty Dumpty principle'. British Journal of Obstetrics & Gynaecology
2002;109:1081-1088.
4. Jarvis GJ. Surgery for genuine stress incontinence. British Journal of
Obstetrics & Gynaecology 1994;101(5):371-374.
5. The MRC COLPO Trial - ISRCTN14969683. In: Register of Current
Controlled Trials; http://www.controlled-trials.com; accessed 19.10.2002.
6. Hospital Episode Statistics. In: Hospital In-Patient Data;
http://www.doh.gov.uk/hes/index.html; accessed 19.10.2002.
7. Tincello DG, Alfirevic Z. Important clinical outcomes in urogynecology:
Views of patients, nurses and medical staff. International Urogynecology
Journal & Pelvic Floor Dysfunction 2002;13(2):96-98.
8. Hollis S, Campbell F. What is meant by intention to treat analysis?
Survey of published randomised controlled trials. British Medical Journal
1999;319:670-674.
9. Fergusson D, Aaron S, Guyatt G, Hebert P. Post-randomisation
exclusions: the intention to treat principle and excluding patients from
analysis. British Medical Journal 2002;325:652-654.
10. Ward K, Hilton P, Browning J. A randomised trial of colposuspension
and tension-free vaginal tape (TVT) for primary genuine stress
incontinence (abstract). Neurourology and Urodynamics 2000;19(4):386-388.
Competing interests:
As declared in our previous publication (BMJ 2002;325:67-70)
Competing interests: No competing interests