Overview of Randomized Controlled Trials in Primary Total Hip Arthroplasty (34,020 Patients): What Have We Learnt?

Aim: To provide an overview of randomized controlled trials (RCTs) in primary total hip arthroplasty summarizing the available high-quality evidence. Materials and Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), we searched the Cochrane Central Register of Controlled Trials (2020, Issue 1), Ovid MEDLINE, and Embase. We excluded nonrandomized trials, trials on neck of femur fractures or revision surgery, systematic reviews, and meta-analyses. Trials that met our inclusion criteria were assessed using a binary outcome measure of whether they reported statistically significant findings. These were then classified according to the intervention groups (surgical approach, fixation, and component design use, among others). Results: Three hundred twelve RCTs met the inclusion criteria and were included. The total number of patients in those 312 RCTs was 34,020. Sixty-one RCTs (19.5%) reported significant differences between the intervention and the control groups. The trials were grouped into surgical approach 72, fixation 7, cement 16, femoral stem 46, head sizes 5, cup design 18, polyethylene 25, bearing surfaces 30, metal-on-metal 30, resurfacing 20, navigation 15, robotics 3, surgical technique 12, and closure/drains/postoperative care 13 RCTs. Discussion: The evidence reviewed indicates that for the vast majority of patients, a standard conventional total hip arthroplasty with a surgical approach familiar to the surgeon using standard well-established components and highly cross-linked polyethylene leads to satisfactory clinical outcomes. This evidence also offers arthroplasty surgeons the flexibility to use the standard and cost-effective techniques and achieve comparable outcomes.

T otal hip arthroplasty (THA) is one of the most successful and cost-effective interventions in ortho-paedic surgery. 1 Since the inception of the modern low friction hip arthroplasty by Charnley 2  institute, little has changed in the fundamentals of this operation. However, significant advances have been achieved in metallurgy and manufacturing processes, particularly with the highly cross-linked polyethylene (PE) ensuring excellent long-term outcomes of THA. 3 Nonetheless, debate continues over the optimal surgical approach, implant fixation, head sizes, or bearing surfaces. National joint registry data play an important role in monitoring implants, measuring performance and survivorship nationwide such as the Scandinavian registries and the United Kingdom national joint registry, which also collects patient-reported outcome measures' data. 4 However, in clinical research, high-quality randomized controlled trials (RCTs) provide strong evidence for the efficacy of healthcare interventions and inform evidence-based medicine. 5,6 In particular, RCTs with results demonstrating clinically or statistically significant differences between two interventions indicate a positive effect of one intervention over another. 7,8 A large number of RCTs have been conducted in THA over the years with only few reporting significant findings reflecting the lack of marginal effects of evaluated surgical interventions. 9 In this systematic review of the literature, we therefore aim to evaluate published RCTs in primary THAs summarizing the available high-quality evidence.

Methods
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), 10 we carried out the electronic searches in January 2018 and updated searches in January 2020. We searched the Cochrane Central Register of Controlled Trials (2020, Issue 1), Ovid MEDLINE (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid MEDLINE, and Versions) (1946-20 January 2020), and Embase (1980-20 January 2020). We limited our searches to the English language literature. In MEDLINE, we combined the subject-specific search strategy with the sensitivity maximizing version of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials. 11 The following search strategy was used [(rct OR randomised OR randomized OR "clinical trial" OR blinded OR "controlled trial").ti,ab*AR-THROPLASTY, REPLACEMENT, HIP/("total hip replacement*" OR "THA"").ti/Document type Clinical Trial OR Controlled Clinical Trial OR Randomized Controlled Trial].
We examined the titles and abstracts of articles identified in the search as potentially relevant trials. We obtained the full texts of trials that fulfilled our inclusion criteria (i.e., RCTs for THA) and those that were unclear from perusal of the abstracts. We excluded nonrandomized trials, trials on neck of femur fractures/ revision surgery, systematic reviews, and meta-analyses. Trials that met our inclusion criteria were assessed by two authors (H.E.M. and S.R.P.) using a binary outcome measure of whether they reported statistically significant findings. These were then classified according to the intervention groups (surgical approach, fixation method, and design) in a narrative review summarizing the evidence. The results were expressed descriptively in numbers and percentages. SPSS 16.0 software (SPSS) was used for descriptive statistical analysis.

Results
The electronic searches produced 5141 records, and additional 6 records were identified from reference lists of some included studies. After removing duplicates and screening abstracts, 952 studies were assessed for eligibility, and 312 RCTs met the inclusion criteria and were included ( Figure 1). The total number of patients in those 312 RCTs was 34,020. A steady increase has been observed in the number of RCTs published per year with the first conducted in the early 1990s to an average of 20 RCTs per year in the 2010s ( Figure 2). Sixty-one RCTs (19.5%) reported significant differences between the intervention and the control groups. The trials were classified according to intervention groups (Table 1).

Surgical Approach
Seventy-two RCTs with 6728 patients evaluated different surgical approaches or related aspects with only five RCTs (6.9%) reporting significant differences between the intervention groups (Table 2). Hamilton et al 12 evaluated the use of implant positioning software with fluoroscopy in anterior THA in 200 patients and reported closer results to target but with longer operative and fluoroscopy time. Takada et al 15 compared direct anterior with anterolateral approaches in bilateral THA in 30 patients at a 1-year follow-up focusing on nerve injury and muscle atrophy measured on CT and MRI. They reported no differences in clinical outcomes despite significant differences in muscle atrophy and increased nerve injury with the anterior approach. Acetabular implant positioning was compared radiographically in 60 patients using supine versus lateral patient positioning through a modified Watson-Jones approach with more accurate cup positioning in the supine position. 13 Moon et al 14 compared two techniques of posterior soft tissue repair in 167 hips (150 patients) at a 28-month follow-up and reported better outcomes and less dislocations with trans-osseous repair compared with gluteus medius/short rotators tendon-to-tendon repair. Finally, Kruse et al 16 compared radiographic outcomes of posterior and lateral approaches in 80 patients and reported that the femoral offset and abductor moment arm were significantly increased when using posterior compared with lateral approach.
Twenty-two RCTs looked specifically at minimally invasive surgery techniques and compared the outcomes with standard techniques including anterior, anterolateral, and posterior approaches; none have reported significant differences in their measured outcomes. The remaining 45 RCTs were as follows (Appendix 1): mini-incisions and two-incision approaches in 13 RCTs, anterior versus posterior approaches in 9 RCTs, anterior versus lateral approaches in 7 RCTs, lateral versus posterior approaches 4 RCTs, variant posterior approaches such as repair of soft tissues or not in 4 RCTs, piriformis sparing approach in 2 RCTs, use diathermy and electrocautery in 2 RCTs, and one RCT for each supercapsular percutaneously assisted approach, trans-trochanteric approach, outpatient anterior approach and patient positioning; none of these 45 RCTs reported any significant differences.

Fixation (Cemented Versus Cementless) of Total Hip Arthroplasty
Seven RCTs compared cemented and cementless THA of different brands with a total of 1271 patients. Only one trial, Corten et al, 17,18 reported significantly better survivorship for cementless THA in their 20-year follow-up report of their 93 patients from an original RCT sample size of 250 patients (P = 0.020). The cementless tapered stem had an extremely good survival rate of 99%.
Radiographs showed evidence of mild stress-shielding around 95% of the cemented stems and 88% of the cementless stems; stress-shielding of grade 3 or greater was seen around the remaining 12% of the cementless stems. The remaining six RCTs reported no significant differences between cemented and cementless THA although their follow-up was only up to 5 years.

Cement Trials
Sixteen RCTs with a total of 979 patients evaluated cement comparing different viscosities or different types of cement restrictors with five RCTs (31.3%) reporting significant findings (   The remaining 11 RCTs reported no significant differences, including one RCT comparing Hardinge cement restrictor with an autogenous bone plug restrictor, one RCT compared the thickness of the cement mantle (thin versus thick), three RCTs comparing fluoride-containing acrylic cement with conventional cement, Palacos, or Palacos G cement. Additional six RCTs made the following comparisons between different types of cement with no significant differences reported; low/medium Simplex P cement versus high-viscosity Simplex AF cement (Stryker-Howmedica), Cemex Rx (

Femoral Stems Trials
Forty-six RCTs with 5242 patients evaluated aspects specifically related to femoral stems. Only three RCTs reported significant differences. Berger et al 24 reported a significantly lower rate of cement mantle deficiencies when using stem centralizer in 60 patients (P , 0.001). In their trial of 39 patients at a 2-year followup, Tanzer et al 25 assessed femoral bone remodeling using dual-energy radiograph absorptiometry after a titanium proximally porous-coated femoral implant with or without hydroxyapatite (HA)-tricalcium phosphate coating. The HA-tricalcium phosphate-coated stems had significantly less femoral bone loss. Luites et al 26      Cup placement time, total fluoroscopy time, and cup position Cups placed using software were significantly closer to the target abduction angle (P , 0.001) with fewer outliers. Cup placement took longer in the software group (P , 0.001), and 2 seconds more total fluoroscopy time (P , 0.001). Takada et al 13 Supine versus lateral position using the modified Watson-Jones approach (n = 60) Cup positioning on radiograph and CT (target abduction 40°) The supine group was significantly more accurate than lateral group (2.4°versus 4.5°; 95% CI 0.7-3.5; P , 0.01

Polyethylene Trials
Twenty-five RCTs with 2216 patients compared different types of PE particularly the effect of cross-linking on wear rates with a long-term follow-up (multiple publications). Ten RCTs (13 studies; Table 4) reported significant differences. Cross-linked polyethylene showed better wear characteristics compared with conventional PE at 5-and 10-and 15-year follow-ups. [30][31][32] Similarly, HXLPE consistently shown to have significantly better wear characteristics across different trials up to a 12-year follow-up [33][34][35][36][37][38][39][40] (Table 4). Vitamin E-infused HXLPE was also shown to have significantly better wear rates across two RCTs with a 3-year follow-up compared with ultra-high-molecular-weight polyethylene (UHMWPE). 41

Metal-on-Metal Total Hip Arthroplasty
Thirty RCTs compared metal-onmetal (MoM) THA with other bearing surfaces in 2912 patients. This was a unique group of trials where nearly all RCTs that looked at metal ions in their reported outcomes found statistically significant higher levels of ions with MoM but similar clinical outcomes and patient-reported outcome measures. Trials that did not report on metal ion levels (10 RCTs) found no significant differences in their reported outcomes comparing MoM with other bearings (Appendix 1).

Hip Resurfacing Versus Total Hip Arthroplasty
Twenty RCTs looked at hip resurfacing in 1762 patients. Only one RCT (5%) reported statistically significant differences. Penny et al 47 compared Articular Surface Replacement (ASR) hip resurfacing prosthesis with THA at a 2-year follow-up in 38 patients and found higher consistently higher metal ions levels with ASR (P # 0.001). The remaining 19 trials reported no statistically significant differences although the majority were short-term follow-ups (2 to 5 years). These included 15 RCTs comparing outcomes of hip resurfacing versus THA; two RCTs compared hip resurfacing with MoM THA; one RCT compared cemented versus cementless femoral stem; and one RCT compared posterior versus anterolateral approach in hip resurfacing (Appendix 1).

Navigation and Robotics
Navigation was evaluated in 15 RCTs with a total of 1158 patients. Three RCTs (20%) reported significant differences with improved cup positioning ( Table 6). The remaining 12 RCTs reported no significant differences including navigated versus free hand techniques for THA in 10 RCTs,

Surgical Technique and Miscellaneous Trials
Twelve heterogeneous RCTs looking at surgical technical aspects of THA are presented in this group with 1098 patients. Five RCTs (41.6%) reported significant findings in favor of using a measuring device to minimize leg length discrepancy, 51 high-efficiency particulate air to reduce colonyforming units within 5 cm of the surgical wound, 52 better acetabular component positioning measured on postoperative CT scan with the use of patient-specific instrumentations, 53 the use of transverse acetabular ligament for cup anteversion and inclination, 54 and the use of digital inclinometer-assisted cup insertion technique 55 (Table 7).
The remaining seven RCTs reported no significant differences and made the following comparisons: sequential versus simultaneous bilateral THA; removal versus retention of subchondral bone plate for cemented cups in two trials; cup insertion with or without inclinometer; the use of abductor shuck versus transosseous pins (a level-caliper system using trans-osseous periacetabular and femoral pins as two fixed points) versus patella electrocardiogram leads to measure intraoperative leg length; plasma-rich platelets versus no plasmarich platelet in bilateral THA; and autologous impaction bone grafting versus traditional technique in cementless THA (Appendix 1).

Skin Closure, Drain, and Postoperative Care
There were 13 RCTs in this group with 2287 patients included. Only one RCT (7.7%) reported significant findings. Rui et al 56 compared staples versus absorbable subcuticular suture for skin closure at a 3-month follow-up in 165 patients. They reported no infections in sutures group versus 2 superficial infections (2.4%) in the staples group. A statistically significant difference was observed in favor of the suture group for time to dry surgical incisions (4.8 versus 5.0 days, P = 0.028), hospital stay (6 versus 12, P , 0.001), and cost saving $82.2 per case. Although shorter surgical time to use staples (24.7 versus 357.7 seconds, P , 0.001), no difference was observed in patients' satisfaction. However, two additional RCTs made similar comparisons and reported no significant difference between staples and sutures (Appendix 1).
Four RCTs evaluated the use of surgical drain postoperatively comparing

Discussion
In this study, we provide a comprehensive overview of 312 RCTs in primary THA. The total number of patients included in those RCTs was 34,020. The most important finding is that only 19.5% of trials reported significant differences between the intervention and the control groups for the outcome measures used by those trials. Different surgical approaches were evaluated in 72 trials, the largest subgroup of trials, with 93% reporting In total, 60 RCTs compared different bearing surfaces including metal-onmetal bearings that have consistently shown raised levels of metal ions and the familiar mode of failure of this particular bearing. The evidence reviewed equally supports the use of metal-on-PE, CoC, and ceramic-on-PE bearings; the latter is further supported by emerging long-term survivorship and registry data. 3,57 Clinical outcomes of hip resurfacing were evaluated in 20 trials in comparison with THA, and functional outcomes were similar at short-to medium-term follow-ups. Trials of navigation techniques show no difference in clinical outcomes although some reported significant differences in radiological outcomes, particularly cup positioning, and a long-term follow-up is needed to see whether this leads to improved clinical outcomes. Finally, skin closure techniques, use of drains, and postoperative weight-bearing status or hip precautions were evaluated in a small number of trials with no significant differences.
Evidence derived from RCTs is based on highly selective populations in a tightly controlled settings and deemed to have the highest reliability. However, most RCTs are short or medium term as obtaining a longterm follow-up is complicated by cost, co-intervention, loss to follow up, and postrandomization variables. 58 Long-term observational studies and data registries, despite their inherent limitations, prove more practical in evaluating long-term outcomes of THA such as survivorship and reoperations and provide a pragmatic overview of clinical practice. [59][60][61] In its 16th annual report, the UK's national joint registry has collated data for over 1 million primary THA with up to a 15-year follow-up. Ceramic-on-polyethylene bearings performing particularly well and the overall revision rates after primary THA have reduced over the last 10 years after the peak of metalon-metal bearings. 57 Similar trends have been reported in other national registries and long-term follow-up studies 3 ; the RCTs included in this study support those findings.
Patient-reported outcome measures (PROMs) play an important role in  65 Others have found only weak-to-moderate correlation between PROMs and patient satisfaction. 66 The International Society of Arthroplasty Registries PROMs working group acknowledges the variation in the specific PROMs used and does not make specific recommendations about which PROMs to use in arthroplasty registries. 67 PROMs are used in many registries to support quality assurance and provide information on value-based care. However, in the context of RCTs, they may not detect the marginal effects of the evaluated interventions.
This is the first study to undertake a comprehensive overview of RCTs in THA. We do, however, acknowledge limitations to its findings. We did not calculate the treatment effect of individual trials with significant statistical findings and whether this correlated with clinically measurable effects. Furthermore, the quality of reporting trials was not addressed as this aspect falls outside the scope of this study. However, reporting bias or publication bias in clinical research is a known phenomenon where data from trials with negative findings are not publicized, and so they remain inaccessible. 68 The prospective registration of trials and public access to study data via results databases had been introduced to minimize the impact reporting bias. 69 The true scale of this bias in the clinical literature is unclear. However, 80% of published RCTs in THA reported no significant differences "negative trials," which may indicate that there is no tendency to overestimate the efficacy and underestimate the risks of the interventions evaluated in those trials.
To conclude, THA is a successful and durable operation that has helped millions of patients worldwide. The early failures encountered in the 1970 to 1980s had been largely addressed in the 1990s and the early 2000s with improved metallurgy and manufacturing processes. The RCT evidence presented indicates that for the vast majority of patients, a standard conventional THA with a surgical approach familiar to the sur-geon using standard well-established components and highly cross-linked polyethylene leads to satisfactory clinical outcomes. This evidence also offers arthroplasty surgeons the flexibility to use the standard and cost-effective techniques and achieve comparable outcomes. Future trials should also focus on preoperative interventions to improve clinical outcomes, an area that is currently lacking in THA trials.