Anterior cruciate ligament reconstruction (ACLR) is complicated by high failure rates in
young, active individuals, which is associated with worse outcomes and higher rates of
osteoarthritis (OA). ACLR failure reduces quality of life (QOL) and has substantial
socioeconomic costs. Therefore, strategies to reduce ACLR failure are imperative. Lateral
extra-articular tenodesis (LET) may provide greater stability; however, its effect on the
rate of graft failure remains unclear, and surgically-induced lateral compartment OA is a
concern given the potential for over-constraint of the joint.
Many surgeons believe that autograft choice for ACLR, with or without LET, does not
affect graft failure. Specifically, bone patella tendon bone (BPTB) autograft has been
perceived to be just as good as a hamstring tendon (HT) graft. However, recent
meta-analyses suggest that BPTB grafts provide better stability, albeit with greater
donor site morbidity. Increasingly, quadriceps tendon (QT) autograft is being used for
ACLR with claims of comparable stability to the BPTB graft without the donor site
morbidity. However, the effects of a QT on graft failure are unknown. Despite its
importance, there has not been an adequately powered study to evaluate if BPTB or QT is
superior to the other in terms of graft failure rates, return to sports, donor site
morbidity, lateral compartment OA and healthcare costs.
Objectives:
Determine if graft type (QT, BPTB, HT) with or without a LET affects:
- - Rate of ACL clinical failure 2 years after ACLR;
- Patient-reported outcomes, muscle function, performance-based measures of function
(hop tests, drop vertical jump) and return to sports;
- Intervention-related donor site morbidity, complications and adverse outcomes;
- Cost-effectiveness of ACLR and LET.
Approach: This is a multicenter, international,
randomized clinical trial that will randomly assign 1236 ACL deficient patients at
high risk of re-injury, to an anatomic anterior cruciate ligament reconstruction
(ACLR) using a BPTB or QT autograft with or without a LET in a 1:1:1:1 ratio. Data
from this study will be combined with data from a recently completed randomized
clinical trial comparing ACLR with a hamstring tendon (HT) graft with or without
LET.
Randomization will be stratified by surgeon, sex, and meniscal status (normal/repaired v
meniscectomy) in permuted block sizes to ensure that any differences in outcome
attributable to these factors are equally dispersed between treatment groups. Each site
will either use traditional or expertise-based randomization. All randomization will use
the web-based application available through the data management center.
Methods to Reduce Biases:
Selection Bias between STABILITY 2 Intervention Groups: We will partially determine
eligibility prior to surgery. Once in surgery, all patients will undergo an examination
under anesthesia and diagnostic arthroscopy to confirm final eligibility. The surgeon
will document evidence of the participant's ineligibility in the surgical report that is
discovered during surgery (e.g. partial ACL rupture where an ACLR is not performed,
multiple ligament reconstruction, chondral lesion requiring more than debridement). The
operative notes for all participants that were consented will be included in the study
database. The study quality control monitors will review the evidence provided by the
operating surgeon (arthroscopic pictures/video of ACL integrity and chondral status) and
recommend that either the participant remain in the study or be withdrawn since they were
never eligible.
At the traditional randomization sites, full randomization occurs during surgery
following arthroscopic evaluation of eligibility, which already serves to reduce the risk
of selection bias. The action of requiring evidence of ineligibility at time of surgery
therefore, reduces the risk of sampling bias (applicability) in traditional randomization
sites. At the expertise-based randomization sites, where randomization to graft type
occurs prior to surgery, this action will prevent unsubstantiated post-randomization
withdrawals prior to randomization to LET or no LET, which reduces sampling bias
(applicability) and selection bias by avoiding unequal exclusions between the LET/no LET
assignment since randomization to LET/no LET occurs after the arthroscopic examination.
In summary, having to provide evidence of eligibility at surgery will serve as a
deterrent for surgeons declaring eligible consenting patients ineligible during surgery,
which serves to reduce the likelihood of sampling and selection bias.
Selection Bias between STABILITY 1 (NCT02018354) and STABILITY 2 Comparisons: STABILITY 1
followed the exact same protocols as are proposed for STABILITY 2 and the two studies
will be performed immediately in series; thus, changes in ancillary care and surgeon
expertise are unlikely. Consequently, analyses that combine data from STABILITY 1 and
STABILITY 2 are unlikely to suffer significant between-study selection biases that are
usually a concern for non-randomized comparisons. Further, to evaluate selection bias
between the STABILITY 1 and STABILITY 2 samples, the baseline characteristics of the
samples will be evaluated to identify any systematic differences between the samples.
Performance Bias, Fidelity & Adherence: Surgeons have agreed upon standardization of
aspects of the surgical interventions that could potentially influence outcomes. All
other aspects of the surgical interventions are meant to be pragmatic and may vary by
surgeon. Aspects allowed to vary are not expected to influence outcome. Further,
randomization is stratified by surgeon so that nuance differences by surgeon are balanced
between groups. In terms of fidelity, all participating surgeons have the necessary
expertise to conduct both surgical procedures (BPTB, QT) if they have elected to
participate in traditional randomization. Surgeons who have a preference for or greater
skill performing one graft type over the other, will participate in expertise-based
randomization and have identified another surgeon with similar expertise/preference
performing the opposite graft type. In terms of performing a LET, all surgeons who have
not completed at least 10 LETs will participate in a cadaver training lab and be required
to complete at least 10 LET procedures prior to randomizing their first patient. The
investigators have agreed upon a protocol for ACL rehabilitation following ACLR. All
patients will receive a copy of the protocol with a standardized referral from their
surgeon for their physical therapist. Deviations from the protocol are not expected to be
different from usual practice and as such patient adherence with rehabilitation protocols
is expected to vary. Given the large sample size, we expect that adherence to
rehabilitation will be balanced between groups and we will adjust the analyses for length
of time in rehabilitation. This study will track the number of rehabilitation sessions
attended, milestones and timing of rehabilitation-specific activities to collect some
adherence and fidelity data.
Detection Bias: An independent surgeon, primary care sports medicine physician, physical
therapist or athletic trainer who is unaware of group allocation will conduct all
assessments of graft stability (primary outcome). Although incisions are unique for each
procedure, patients will wear a tubigrip sleeve over both knees to conceal the incisions
and reduce bias in assessments that require side-to-side comparisons, including the
primary outcome. Data assessors for other outcomes will also be kept unaware of group
allocation using this method.
Intention-to-Treat Principle: Patients will be analyzed within the group to which they
were randomized regardless of graft type received or adherence to protocols.
Attrition Bias: From STABILITY 1, we have complete data on 95% of the 618 patients who
are at least 2 years postoperative demonstrating that we are capable of successful
recruitment and retention in a study of this magnitude. We will use the same measures to
maximize completeness of follow-up.Statistical Methods:
Sample Size: We estimate that the absolute risk of graft failure (as defined above) in
the ACLR will range from 25-35%. STABILITY 1 supports this estimate. We consider a
relative reduction in graft failure rate of at least 40% to merit a change in practice
(i.e. of sufficient magnitude to warrant the additional costs of adding a LET). With 255
patients per group and a type I error rate of 1% we would have 80% power to detect a
relative risk reduction in rate of failure of 40% or greater in those with LET assuming
the graft failure rate in ACLR is 33%. We have used a small type I error rate of 1% to
reduce the risk of multiple comparisons error. To reduce the risk of losing precision
from withdrawal and lost-to-follow-ups, we will over recruit by 15%, for a total of 309
per group or 1853 participants in total (combined STABILITY 1 and STABILITY 2 data).
While not all sites have the infrastructure to conduct the isokinetic quadriceps and
hamstring tests (13 sites) and in vivo kinematics during the DVJ (one site), these
outcomes are reported using a continuous metric and therefore do not require as large a
sample size as the proportional primary outcome.
Statistical Analyses: The data collected through this study will be pooled with the data
from STABILITY 1 for analysis (n=1800). To determine whether graft type (QT, BPTB, HT)
with or without a LET offers a greater reduction in rate of failure following ACLR
(primary research question), we will use a random-effects logistic regression with
failure following ACLR at each visit (yes/no) as the outcome where fixed effects include
intervention group, meniscal repair status, sex and time (as a categorical variable) and
random effects include patient and surgeon. We will conduct a similar analysis for
secondary outcomes like return-to-activity and donor site adverse events, as both are
binary outcomes. For each continuous secondary outcome including patient-reported
outcomes (PRO) scores, measures of impaired range of motion (ROM) and muscle strength,
performance-based measures of physical function, and lateral compartment joint space
narrowing, we will conduct a linear mixed-effects model where the fixed effects include
ACLR group, meniscal repair status, sex and time (as a categorical variable) and random
effects including patient and surgeon. For missing data, we will evaluate whether data
are missing completely at random by comparing the available data (especially at baseline)
for those with and without missing data at follow-up. We will use multiple imputation
techniques to handle missing data.
Sex-based analysis: To compare failure between HT+LET and other graft options (BPTB or
QT) for males and females separately, we will conduct a random-effects logistic
regression with the same fixed and random effects as in the primary analysis.
Health services analyses: We will assign the average procedure cost for an ACLR surgery
at each participating institution with the additional cost of the lateral extra-articular
tenodesis for those patients randomized to the LET group. Patients who undergo a revision
ACLR will complete a healthcare resource diary to capture additional direct and indirect
costs. We will conduct a cost-effectiveness analysis from a healthcare payer and societal
perspective using quality-adjusted life years (QALY) as our effectiveness outcome at two
years postoperative. We will estimate the incremental net benefit (INB) of ACLR + LET
using a random effects multilevel model. To characterize the statistical uncertainty
around our estimate of INB, we will use an extension of the standard net benefit
regression framework using the hierarchical data to generate location-specific net
benefit curves, and cost-effectiveness acceptability curves.
