STABILITY 2: Anterior Cruciate Ligament Reconstruction +/- Lateral Tenodesis With Patellar vs Quad Tendon

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.