Evaluation of two vaginal, uterussparing surgical methods for pelvic organ prolapse reconstruction: modified Manchester operation (MM) and sacrospinal hysteropexy (SSH).

INTRODUCTION/RATIONALE:
POP is highly prevalent (50% of vaginally parous women) and the symptoms have a
high impact on quality of life. 20% of
Dutch women will undergo POP surgery during life time. According to guidelines,
first choice surgical treatment of POP is a
vaginal POP operation. According to Kiwacharity, more than 17.000 of these
operations are performed yearly in the
Netherlands. Vaginal POP operations consist of vaginal hysterectomy (VH),
Modified Manchester operation (MM) or
sacrospinous hysteropexy (SSH), in combination with colporrhaphy when
indicated. The most distinct difference between the
operations is that in VH the uterus is removed and in SSH and MM the uterus is
attached to different pelvic ligaments.
These 3 types of surgery have lead to practice pattern variation (PPV) between
hospitals and physicians. PPV is defined
as a difference in care that cannot be explained by the underlying medical
condition. In general PPV is considered to be a
problem in controlling medical costs.
The comparison VH versus SSH has been made in the randomized SAVE-U study. That
study showed non-inferior
effectiveness of SSH, but shorter operation times in SSH. In combination with a
patient*s preference for uterus preservation,
the SAVE-U publications have provided arguments to choose for uterus sparing
surgery. However, it is still unclear whether the
2 operations (SSH and MM) have equal outcome.
This study proposal is on a comparison of the two uterus sparing techniques
(effectiveness and costs). We hypothesise that the
effectiveness of SSH is non-inferior to MM, but with shorter operation times.
The study will reveal whether the exsisting PPV is
unwanted or not significant in terms of effectiveness and cost.
HEALTH CARE EFFICIENCY PROBLEM:
Vaginal POP operations are subject to uncontrolled PPV due to lack of evidence.
Only 13% of women prefered
hysterectomy, but in 2009 in 60% the uterus was removed (range 2 and 100%
between hospitals). Between 1997 and
2009, the rise in MM and SSH was more than 5-fold. In the two hospitals in
Nijmegen, 92% and 36% of POP procedures was
a MM, and in some Dutch centres no MM or SSH is performed at all. The variation
and the fluctuation is not based on evidence
on a better outcome. The choice of operation thus depends mainly on the
physican*s preference. This was confirmed in a
questionnaire study among 161 (uro)gynaecologists in 2011. The physician*s
preference for VH, SSH or MM was equally
devided in women with stage 2 uterine descent (varying from 25-34%). Evidence
based deimplementation of one the
procedures or shared decision making between patient and physician is not
possible at this moment.

Objective:
The life-time risk for POP surgery is 20%, and 30% of these women will need
surgery because of a recurrence. Vaginal
POP surgery (VH, SSH and MM) is the first choice surgical treatment. The
numbers of uterus sparing operations (SSH and
MM) are rising more than 5-fold in recent years, at the expense of VH. Doctor*s
preference was equally divided between the
three procedures in the patient group as defined in the present study proposal.
There is maximal practice pattern variation
dictated by this doctor*s preference. Shared decision making is not possible
due to this lack of evidence, mainly on
effectiveness of MM. MM is still performed approximately 3.000 times yearly in
the Netherlands, which makes it undesirable to
neglect this knowledge gap.
This project will fill the knowledge gap on the effectiveness and costs of SSH
versus MM. There are no other peer reviewed
publications, on going or planned studies on the topic. Guidelines do not
advise one techniques over the other.
(Uro)gynaecologists do not expect relevant differences in the main outcomes
(composite outcome). At this time point, we
do not know whether the substantial practice pattern variation in the
Netherlands is detrimental or not. This study will provide
the answer to that question, and may lead to the need for deimplementation of
one of the procedures.
Hypothesis: composite outcome of SSH after 2 years is non-inferior to MM but
with shorter operation times in SSH.
Research questions:
1. Is SSH non-inferior to MM in women with signs and symptoms of POP in terms
of composite outcome?
The composite outcome defines a successful operation in case of subjective and
objective success achieved in the absence of
re-operation.
2. In case SSH is non-inferior, is deimplemenation of MM indicated based on a
difference in costs in favour of SSH?

DESIGN
The study is designed as a non-inferiority study, randomising each eligible
patients giving informed consent for either the
Modified Manchester (MM) or Sacrospinous Hysteropexy (SSH) operating technique.
The follow up period is 2 years.

The H0 for this trial is that SSH is non-inferior to MM regarding composite
outcome for success. We consider SSH
inferior when the absolute difference in success rate exceeds 9% compared to
the expected success rate of 89% - this is
comparable to a relative difference of 0.80/0.89 is 0.90. If the left border
does not exceed the left border of the 9% CI with the
pre-defined threshold of 0.90 for inferiority we will consider SSH to be
non-inferior to MM.
The analysis will be by intention-to-treat and per protocol. The primary
outcome is defined as the composite of success (dichotomous) 1 year
after surgery.
Results of secondary outcomes will be described as frequencies, absolute and
relative risks, and hazard ratio*s for
dichotomous outcomes as appropriate, together with confidence intervals.
Continuous outcomes will be described by mean/
median, mean difference, or standardized mean difference.
Subgroup analyses will be adjusted for relevant prognostic factors. No interim
analyses for effectiveness, adverse effect, or
futility are planned. A Statistical Analysis Plan will be completed early
during the trial, including ICT standards and a
data-monitoring plan.
Missing values are minimised though active trial monitoring within the
Consortium. Data are routinely prospectively collected.
The software Castor (https://nl.castoredc.com) will be used to collect the
questionnaire data. Therefore, the likelihood of
missing values for which data eventually cannot be obtained is very limited. If
circumstance require however, a limited amount
of missing values (if missing not at random) may be imputated. In pertaining
situations, sensitivity analyses will be carried out to
describe the effect of imputation.

SAMPLE SIZE CALCULATION
Sample sizes of 193 in group one and 193 in group two achieve 80% power to
detect a
non-inferiority margin difference between the group proportions of -0.0900. The
reference group proportion is 0.8900. The treatment group proportion is assumed
to be 0.8000 under the null hypothesis of inferiority. The power was computed
for the case when the actual treatment group proportion is 0.8900. The test
statistic used is the one-sided Z test (unpooled). The significance level of
the test was targeted at 0.0250.
The 9% non-inferiority margin was motivated by the margins used in two other
large national studies SAVE-U (7%) and PEOPLE study (10%).
The anticipated number of patients is considered both feasible in terms of
number of
patients available, willingness to participate and maximum available funding
(see also Feasibility).

INTERVENTION(S)
Sacrospinous hysteropexy (SSH):
After opening the posterior vaginal wall, the pararectal space is explored at
the right side and the sacrospinous ligament is
identified. The posterior side of the cervix is attached to the sacrospinous
ligament with 2 non-absorbable Prolene sutures
approximately 2 cm medial of the ischial spine (to prevent damage to the
pudendal nerve). Anterior and posterior colporrhaphy
as indicated.
Apeldoorn: https://www.youtube.com/watch?v=ySSfy2A1_RM
USUAL CARE/COMPARISON
Modified Manchester operation (MM):
The procedure consists of extraperitoneal plication of the uterosacral
ligaments (and cardinal where possible) with use of three
or four Vicryl 1 sutures and amputation of the cervix. The most cranial suture
is fixated through the posterior fornix of the
vagina. Anterior and posterior colporrhaphy as indicated.
Videoclip Enschede: https://www.youtube.com/watch?v=HYzWm7rRjho.

Anaesthesia, antibiotics and thrombosis prophylaxis, patient*s position on the
OR table, postoperative catheterisation and
vaginal packing and standards for postoperative hospitalisation are similar for
the procedures. Local protocols in the including
hospitals will be checked for differences between the treatments (e.g. duration
of hospitalisation). In case of differences the
protocols will be made uniform (as far as possible) before the start of the
study, but will otherwise be left to the discretion of the
surgeon.

Burden: follow up with physical (gynaecological) examination at 1 and 2 years
after surgery and questionnaires at 12 weeks, 1 and 2 years is not standard in
all Dutch hospitals. This holds true for 5 and 10 years after surgery as well.
Risks: not applicable.