Internal fixation treatments for intertrochanteric fracture: a systematic review and meta-analysis of randomized evidence

The relative effects of internal fixation strategies for intertrochanteric fracture after operation remain uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to address this important issue. We searched PubMed, EMBASE and CENTRAL for RCTs that compared different internal fixation implants in patients with intertrochanteric fracture at 6-month follow-up or longer. We ultimately included 43 trials enrolling 6911 patients; most trials were small in sample sizes and events. Their risk of bias was generally unclear due to insufficient reporting. Because of these, no statistically significant differences were present from most of the comparisons across all the outcomes, and no definitive conclusions can be made. However, a number of trials compared two commonly used internal fixation strategies, gamma nail (GN) and sliding hip screw (SHS). There is good evidence suggesting that, compared to SHS, GN may increase the risk of cut out (OR = 1.87, 95% CI, 1.08 to 3.21), re-operation (OR = 1.61, 95% CI, 1.02 to 2.53), intra-operative (OR = 3.14, 95% CI, 1.34 to 7.35) and later fractures (OR = 3.67, 95% CI, 1.37 to 9.83). Future randomized trials or observational studies that are carefully designed and conducted are warranted to establish the effects of alternative internal fixation strategies for intertrochanteric fracture.


Risk of bias assessment. We assessed the risk of bias of RCTs using a modified version of the Cochrane
Collaboration's tool 15 . The items included random sequence generation, allocation concealment, blinding of participants, surgeons or outcome assessors, completeness of outcome data, and selective reporting. We included two additional items regarding "standardization of the operative procedures" and "surgeons' experience clearly defined with operations" because the validity of findings from surgical RCTs depends largely on quality of operation and surgeons' experience 16 . Data extraction. We extracted the following data from each of the eligible studies: study characteristics (publish year, simple size, country, length of follow up), patient characteristics (gender, age, type of fracture); interventions (intramedullary and extramedullary treatments) and outcomes (quality of life scores, function scores, mortality, cut out, non-union, reoperation, operative fracture, later fracture, wound infection, embolism, operative time, blood loss and hospital stay) Data analyses. In the analysis of quality of life data, we reported the data at the baseline, end of the follow up, and the change from the baseline. For functional score data, because of the scanty in the reporting of the baseline data, we compared means at the end of follow up of those outcomes between treatment and control groups, assuming that the randomization has well achieved the balance of the baseline between groups. For each of the comparison, we pooled the quality of life data and the functional scores using weighted mean difference (MD) or standardized mean difference (SMD) if varying measures were used. In the analysis of the operation time, blood loss, and hospital stay, we treated each of the outcome measures as normally distributed, and pooled the mean differences for each of the comparison, and reported 95% confidence intervals. We also pooled, for each of the comparison, the trial data regarding adverse events.
In the meta-analyses, we applied the random-effects model using Mantel-Haenszel method. We examined heterogeneity by Cochran's Q test and I 2 statistic. Where possible, we conducted, for each meta-analysis, a pre-defined subgroup analysis by fracture types (stable fractures vs. unstable fractures by AO/OTA classification) to explore source of heterogeneity.
We performed sensitivity analyses by using alternative pooling methods (Peto method vs. Mantel-Haenszel method applicable to dichotomous data) and alterative statistical model (random vs. fixed effect). We performed the data analysis by the RevMan 5.3.

Results
Characteristics of included studies. The search yielded 3,397 potential relevant reports. After screening of titles and abstracts, 234 records were retrieved for judging final eligibility. We eventually included 43 RCTs involving 6911 patients (Fig. 1). These trials were conducted in 18 countries, of which 4 were international trials. The sample sizes ranged from 40 to 600, and the length of follow up from 6 to 40 months.
Among those trials, 52.4% (3625/6911) of the participants were female; the mean age ranged from 53.9 to 84.3 years; 30 trials (69.8%) recruited both stable and unstable fractures (n = 5010), 12 trials explored the effects of devices on unstable patients (n = 1695), and 1 trial did not report the fracture type of participants (n = 206) ( Table 1). Those 43 trials investigated 11 internal fixation treatments, including GN, ACE nail, holland nail, PFN, PFNA, IMHS, SHS, PCCP, Medoff sliding plate, Targon proximal femoral and LISS. The types of implants under assessment varied considerably across studies; few studies tested a same comparison. The details of comparisons were presented in Table 1.

Effects on quality of life and functional measures. Quality of life scores (QoL scores). Four trials
(n = 420) used EuroQol 5D (EQ-5D) and Short Form (36) Health Survey (SF-36) to measure the effects of internal fixation treatments on the quality of life [17][18][19][20] , all of which were small in sample sizes. Two studies provided the baseline and follow up date on quality of life 17,19 ; compared to the baseline, the scores at the end of follow up decreased. In the comparison of the data at the end of follow up, GN group had a significant higher score than SHS group in one trial reporting EQ-5D (MD: 0.12, 95%CI 0.02 to 0.22); in another small trial, no significant difference in the SF-36 was present between GN and PFNA ( Table 2). The other two studies neither provided the data regarding standard deviation nor baseline.
The comparison of means at the end of follow up showed that patients at GN group had a higher score compared to those at SHS group (SMD: 0.23, 95%CI 0.01 to 0.46, I 2 = 22%), but had a lower score than PFNA group     The pooling analysis suggested that SHS was associated with a lower risk of non-union compared to IMHS (1/228 vs. 9/246; OR: 0.15, 95%CI 0.03 to 0.87, I 2 = 0%), but did not found statistically significant differences in other comparisons, again mostly because of the small number of events and sample sizes (Table 4).

Discussion
Our study has identified a wide variety of internal fixation implants for patients with intertrochanteric fracture, among which sliding hip screw (SHS) and gamma nail (GN) were the most commonly investigated treatment options, as evident from the trials. The other implants, including percutaneous compression plate (PCCP), proximal femoral nail antirotation (PFNA), and proximal femoral nail (PFN), also are often investigated.
The findings from those trials suggested that substantial uncertainty regarding the relative effects -both benefits and harms -remain among those alternative internal fixation strategies, except only a few comparisons, because of the small number of sample sizes with the vast majority of trials and the serious limitations that threat the validity (e.g. failure to conceal treatment allocation).
The quality of life and functional status are of important interest to surgical treatment and are often used in orthopedics surgical trials [60][61][62][63][64] . However, our review identified under-reporting of these outcomes. In the trials having reported these two outcomes, the completeness of data remains less satisfied in most circumstances -many trials failed to report the baseline data and the change from baseline; even if reported, the standard deviations were not available. All those limitations have made fair comparison of alternative internal fixation strategies less likely. Given the current body of evidence, it is uncertain if the quality of life would be improved after the surgical interventions, and which of surgical treatment would achieve better quality of life. In our analyses of the functional scores, the findings similarly suggested a lack of evidence, and no definitive conclusions can be made for most of the comparisons. However, it seems from the analyses that patients receiving PFNA might achieve better functional status after surgery than those receiving GN or SHS. This finding was preliminary given the limitations of the included trials.
The trials extensively reported complications of internal fixation treatments. However, due to the small sample sizes and methodological limitations, the current body of evidence is inadequate to draw clear conclusion for most of the comparisons. The analyses suggested substantial uncertainty of relative effects on complications between internal fixation strategies. However, a number of trials compared GN and SHS. The analyses consistently suggested that patients receiving GN may have significantly higher risk of complications than those SHS, including the risk of cut out, operations, intra-operative fracture, and later facture. The consistency of findings across studies and outcomes, and the relatively large magnitude of effect increases the credibility of this finding. A few other studies also suggested that SHS might have a lower risk of non-union, but have a higher risk of embolism than PCCP.  These findings were, however, fragile given the small number of events and sample sizes, as well as the potential risk of bias those studies pose. A number of trials also reported procedure measures (operation time, blood loss, and hospital stay). The findings were however inconsistent across studies, which resulted in substantial heterogeneity. The presence of the varying procedural outcomes across studies may represent the differential levels of expertise among the surgeons participating in those trials. Overall, the results suggested patients undergoing PFNA may have shorter operative time, and patients undergoing SHS may have more blood loss than other extramural implants.
Compared to the Cochrane systematic review that compared intramedullary nails with SHS for extracapsular hip fractures 14 , we excluded subtrochanteric fractures and assessed more extramedullary implants. The Cochrane Review conducted in 2010 included 43 RCTs that set no limit regarding the length of follow up. They found that the SHS was a better fixation device for the intertrochanteric fractures than nails. They also suggested intramedullary nails have advantages over extramedullary plates/screws for some unstable intertrochanteric fractures. Considering a wide variety of implants with inconsistent outcomes and low precision of estimate effects, we suggest that cautions need to be taken in drawing any definite conclusions.
We conducted a comprehensive systematic review using rigorous methods. However, there are a few limitations. First, because of the limited availability of data, we compared means of functional scores at the end of follow up between treatment groups. We assumed that the data at baseline were well balanced between groups. However, this assumption may not always be hold. Second, the trials we included in the analysis suffered from important methodological limitations, as many other surgical trials. The potential risk of bias that those trials poses has weakened our inference of the treatment effects. Third, most of the trials included in our analyses were small in sample sizes. This has resulted in imprecise estimation of effects, and definitive conclusion is unlikely for most of the comparisons. Fourth, due to the limited evidence with different types of fractures (69.7% of studies did not take into account of the fracture stability), we were unable to explore if the treatment effects might differ by fracture types.
In conclusion, due to the small number of events and sample sizes and serious limitations that those trials pose, the current body of evidence is inadequate to establish the relative effects -including quality of life, functional scores, and complications -of all of the alternative internal fixation strategies. However, the evidence suggests that patients undergoing GN may have a higher risk of complications than those receiving SHS. Future trials that are adequately powered and well designed and conducted are warranted to fairly test the effects of the different surgical treatments. Observational studies that are carefully collect and analyze the data may also provide important insights regarding the effects of the surgical treatments.