Annemarie de Zoete

Background: Chronic low back pain is the leading cause of years lived with disability worldwide. Although spinal manipulation therapy (SMT) is recommended in clinical guidelines and supported by randomised clinical trials (RCTs), systematic review conclusions have not changed despite a growing evidence base. This trial sequential analysis evaluates the extent of research waste in this field by identifying when sufficient evidence had been gathered. Methods: We report a Trial Sequential Analysis using data from the Cochrane review on SMT. This methodological approach assesses whether statistically significant conclusions can be drawn from accumulating evidence by plotting Z‐curve graphs with monitoring boundaries; where the Z‐scores' fall indicates the benefit, harm or futility of the intervention. Trial Sequential Analysis estimates a required information size, analogous to optimum sample size in a single trial, based on the data. Our primary analysis explored whether conclusions have been drawn for SMT versus other conservative treatments for pain and functional status at 1 month. Results: We included, 60 RCTs ( N = 10,312). For the effect of spinal manipulative therapy versus conservative treatments for pain at 1 month, the futility and information size boundary was crossed in 2004, and in 2002 for functional status. At longer follow‐up times, these boundaries were reached at similar dates. Conclusions: RCTs from as early as 2002 have not added to our understanding of the effectiveness of spinal manipulative therapy for chronic low back pain and functional status and therefore constitutes research waste. Conducting further RCTs in this field without a novel research question should be avoided. Significance Statement: This important research quantifies research waste in the field of chronic low back pain, a condition affecting billions worldwide. We advocate for trials addressing novel questions to ensure finite resources go towards effective treatments rather than producing redundant evidence; upholding research ethics. Highlighting innovative use of trial sequential analysis will provide a model for visually and quantitatively demonstrating research waste which if utilised across disciplines can ensure research prioritisation, increased production of high‐value evidence‐based medicine for patients, ultimately improving outcomes.

Rationale Many therapies exist for the treatment of chronic low back pain (LBP), including spinal manipulative therapy (SMT), which is a worldwide, extensively practised intervention. The effectiveness of SMT for chronic LBP is not without dispute. This Cochrane review is an update of a Cochrane systematic review published in 2011. Objectives To evaluate the benefits and harms of SMT compared to (1) sham SMT/placebo intervention, (2) no treatment, and (3) other conservative interventions in people with chronic LBP (18+ years old). Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, two other databases, and two trial registers up to 18 October 2024, unrestricted by language. We also screened the reference lists of all included studies and relevant systematic reviews, and approached content experts to identify potentially missing studies. Eligibility criteria We included randomised controlled trials (RCTs) that examined the effect of spinal manipulation or mobilisation in adults with chronic LBP compared to sham SMT/placebo, no treatment, and other conservative interventions. We placed no restrictions on the setting. We excluded studies that exclusively examined sciatica. Outcomes Our critical outcomes were pain, functional status, and adverse events. The primary time point was one month for pain and functional status. We evaluated adverse events at the end of the intervention. Risk of bias We assessed bias in the included studies using the original Cochrane risk of bias tool (RoB 1). Synthesis methods Where possible, we synthesised results using meta‐analysis with a generic inverse‐variance approach and random‐effects models; otherwise, we used narrative synthesis. We assessed the certainty of evidence using the GRADE approach. Our main comparisons were SMT versus (1) sham SMT/placebo treatment, (2) no treatment, and (3) other conservative interventions at one month. We converted all pain scales to a 100‐point scale. Included studies Seventy‐six RCTs (11,866 participants) met our inclusion criteria, 50 (66%) of which were not included in the previous version of this review. Seventeen trials (2021 participants) compared SMT to sham SMT/placebo, and four trials (435 participants) compared SMT to no treatment. Most trials (43, including 8291 participants) examined the effect of SMT compared to other conservative interventions. The remaining trials examined other comparisons. Treatment allocation was appropriately conducted in just four sham SMT/placebo‐controlled trials (24%), while only six trials 'blinded' participants to the intervention (35%), indicating a high risk of selection and performance bias. Similarly, the no‐treatment controlled trials were as susceptible to selection bias (50%) and performance bias (75%). All trials were conducted in high‐income (n = 53) or middle‐income (n = 23) countries. In most studies, the population was middle‐aged and included men and women. Synthesis of results SMT versus sham SMT/placebo We found very low‐certainty evidence (downgraded for inconsistency and study limitations) that SMT may result in a small reduction in pain compared to sham SMT/placebo at one month (mean difference (MD) ‐7.01, 95% confidence interval (CI) ‐12.48 to ‐1.53; I² = 94%; 16 studies, 1570 participants) and very low‐certainty evidence (downgraded for study limitations and inconsistency) that SMT may result in a medium improvement in functional status compared to sham SMT/placebo at one month (standardised mean difference (SMD) ‐0.41, 95% CI ‐0.69 to ‐0.13; I² = 82%; 13 studies, 1416 participants), but the evidence is very uncertain. SMT versus no treatment We found very low‐certainty evidence (downgraded for study limitations, inconsistency, and imprecision) that SMT may result in a medium reduction in pain compared to no treatment at one month (MD ‐13.99, 95% CI ‐27.33 to ‐0.66; I² = 89%; 4 studies, 325 participants), but the evidence is very uncertain. We found low‐certainty evidence (downgraded for study limitations and imprecision) that SMT may result in a large improvement in functional status compared to no treatment at one month (SMD ‐0.84, 95% CI ‐1.32 to ‐0.35; I² = 71%; 4 studies, 312 participants). SMT versus other conservative interventions Low‐certainty evidence (downgraded for inconsistency) indicated that SMT may result in little to no difference in pain (MD ‐4.72, 95% CI ‐8.26 to ‐1.17; I² = 89%; 31 studies, 4109 participants) and may result in a small improvement in functional status (SMD ‐0.25, 95% CI ‐0.38 to ‐0.11; I² = 73%; 28 studies, 3940 participants) compared to other conservative interventions at one month. These effects, however, should be interpreted with caution due to the substantial statistical heterogeneity for which there is no clear explanation. Less than half of the studies (47%) reported on adverse events, of which 12 studies reported these systematically. Adverse events in the SMT group were limited to muscle soreness, stiffness, and/or transient increase in pain. None of the studies registered any serious complications related to either the experimental or control group treatment. The evidence is very uncertain about the adverse effects of SMT. Authors' conclusions When SMT is compared to sham SMT/placebo, it may result in a small improvement in pain and medium improvement in functional status in adults with chronic low back pain. When compared to no treatment, SMT may result in a medium improvement in pain and a large improvement in functional status. When compared to other conservative interventions, SMT may result in little to no difference in pain and a small improvement in functional status. The evidence is of low to very low certainty, largely due to the fact that the effects of SMT were examined in trials conducted in different settings and populations, with different types of SMT technique, dosage, and frequency of treatment. Continuing to conduct RCTs in the same manner will neither strengthen the evidence nor our confidence in it. Funding This Cochrane review had no dedicated funding, only 'in‐kind' support from the Department of General Practice, Erasmus Medical Center, Rotterdam, Netherlands, and the Department of Health Sciences, Faculty of Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Science Research Institute, Netherlands. Registration Protocol (2009): DOI: 10.1002/14651858.CD008112 Original review (2011): DOI: 10.1002/14651858.CD000447.pub2

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of aerobic exercise on pain, function, quality of life, psychological functioning, and adverse events, compared with placebo, sham treatment, attention control, or no treatment.

Background: Chiropractors commonly provide care to people with low-back pain (LBP). The aim of this survey was to determine the opinions and beliefs of chiropractors regarding the support and management of LBP. We also investigated whether their management is in accordance with the three most commonly recommended approaches to LBP based upon international guidelines (i.e. advice regarding return-to-work, limit bedrest, and stay active). Methods: A web-based survey was sent out in 2013 to collect data from registered Dutch and Belgian chiropractors. In addition to providing a description of their sociodemographic and practice characteristics, chiropractors were asked to complete six patient vignettes representing people with LBP who typically present to a chiropractor. The respondents indicated which intervention(s) they would recommend or undertake. Based upon these vignettes, we were able to determine whether their management approach adhered to clinical guidelines. Generalized mixed models were used to explore guidelines adherence and their relationship to chiropractors’ characteristics. Results: In total, 60% (n = 203/340) of the chiropractors who were invited, chose to participate. Chiropractors reported applying a chiropractic adjustment in 90% of all vignettes, while the advice to exercise varied from one-third in the chronic cases to approximately half of those with acute LBP. More than 75% of the chiropractors would initially treat LBP 1–2 times a week. More than 90% of the chiropractors advised against bedrest. Overall, self-reported adherence to clinical guidelines for all six vignettes was [64.5% (CI 58.7–70.0)]. Adherence in the chronic vignettes [73.4% (CI 66.7–79.2)] was better than in the acute vignettes [55.9% (CI 50.5–61.1)]. Importantly, regarding recommended approaches to LBP, chiropractors more consistently followed guidelines regarding advice to limit bedrest [98.5% (CI 97.3–99.1)] than advice to stay active [77.5% (CI 72.3–81.9)] or return-to-work [59.4% (CI 55.2–63.4)]. Finally, Dutch chiropractors were more likely to adhere to the guidelines than Belgian chiropractors. Conclusions: Chiropractic adjustments were the most common self-reported treatment modalities supplemented by exercise in the management of LBP patients. Two-thirds of the chiropractors reported adhering to the guidelines regarding management and advice for LBP patients. Practitioners should improve guideline adherence, particularly for acute LBP cases, and when advising on return-to-work.

The purpose of this study was (1) to describe diagnostic imaging in Dutch and Belgian chiropractic practice in general, (2) to estimate adherence to the diagnostic imaging guidelines for patients with low back pain (LBP) via vignettes, and (3) to evaluate factors associated with diagnostic imaging and adherence to the guidelines. We used a web-based survey to collect sociodemographic data, practice characteristics, amount of imaging, opinions, and indications for requesting imaging from registered Dutch and Belgian chiropractors in 2013. Additionally, adherence to imaging guidelines for LBP was assessed by 6 vignettes in patients with LBP. Multivariable regression analyses were conducted to explore associations between characteristics of chiropractors and the use of imaging. Generalized mixed models were used to explore guidelines adherence and their relationship with chiropractor's characteristics. The overall response rate was 60% (n = 203 out of 340). In total, 83% of chiropractors viewed diagnostic imaging in general as an important part of their practice. It is important to note that Dutch and Belgian chiropractors are not allowed to refer directly for imaging. Chiropractors reported that they would like to have imaging in 42% of their patients. Imaging had already been performed in 37% of patients before the first visit and was ordered by another health care provider (ie, general practitioner or medical specialist). The most common indication for ordering imaging was exclusion of contraindications (73%). The most common reason against imaging was the perceived limited value (45%). Many chiropractors (71%) were familiar with imaging guidelines. Adherence to the imaging guidelines for LBP based upon the vignettes was 66%. Dutch chiropractors and chiropractors with less than 10 years in practice demonstrated better adherence to guidelines and imaging use as compared with Belgian and those with more than 10 years of experience. Most Dutch and Belgian chiropractors reported that imaging in general was important in chiropractic practice. Self-reported indications for ordering diagnostic imaging were in line with the imaging guidelines in the majority of cases. We found some variances between Belgian and Dutch chiropractors and years of experience related to guideline adherence.

Study Design.: Individual participant data (IPD) meta-analysis. Objective.: The aim of this study was to identify which participant characteristics moderate the effect of spinal manipulative therapy (SMT) on pain and functioning in chronic LBP. Summary of Background.: The effects of SMT are comparable to other interventions recommended in guidelines for chronic low back pain (LBP); however, it is unclear which patients are more likely to benefit from SMT compared to other therapies. Methods.: IPD were requested from randomized controlled trials (RCTs) examining the effect of SMT in adults with chronic LBP for pain and function compared to various other therapies (stratified by comparison). Potential patient moderators (n = 23) were a priori based on their clinical relevance. We investigated each moderator using a one-stage approach with IPD and investigated this interaction with the intervention for each time point (1, 3, 6, and 12 months). Results.: We received IPD from 21 of 46 RCTs (n = 4223). The majority (12 RCTs, n = 2249) compared SMT to recommended interventions. The duration of LBP, baseline pain (confirmatory), smoking, and previous exposure to SMT (exploratory) had a small moderating effect across outcomes and follow-up points; these estimates did not represent minimally relevant differences in effects; for example, patients with versus recommended therapy for the outcome pain (mean differences ranged from 4.97 (95% confidence interval, CI: −3.20 to 13.13) at 3 months, 10.76 (95% CI: 1.06 to 20.47) at 6 months to 5.26 (95% CI: –2.92 to 13.44) at 12 months in patients with over a year LBP. No other moderators demonstrated a consistent pattern across time and outcomes. Few moderator analyses were conducted for the other comparisons because of too few data. Conclusion.: We did not identify any moderators that enable clinicians to identify which patients are likely to benefit more from SMT compared to other treatments. Level of Evidence: 2

Chronic low back pain (LBP) is the leading cause of pain and disability, resulting in a major socioeconomic impact. The Cochrane Review which examined the effect of spinal manipulative therapy (SMT) for chronic LBP concluded that SMT is moderately effective, but was based on conventional meta-analysis of aggregate data. The use of individual participant data (IPD) from trials allows for a more precise estimate of the treatment effect and has the potential to identify moderators and/or mediators. The aim is (1) to assess the overall treatment effect of SMT for primary and secondary outcomes in adults with chronic LBP, (2) to determine possible moderation of baseline characteristics on treatment effect, (3) to identify characteristics of intervention (e.g., manipulation/mobilization) that influence the treatment effect, and (4) to identify mediators of treatment effects. All trials included in the Cochrane Review on SMT for chronic LBP will be included which were published after the year 2000, and the search will be updated. No restrictions will be placed on the type of comparison or size of the study. Primary outcomes are pain intensity and physical functioning. A dataset will be compiled consisting of individual trials and variables included according to a predefined coding scheme. Variables to be included are descriptive of characteristics of the study, treatment, comparison, participant characteristics, and outcomes at all follow-up periods. A one-stage approach with a mixed model technique based on the intention-to-treat principle will be used for the analysis. Subsequent analyses will focus on treatment effect moderators and mediators. We will analyze IPD for LBP trials in which SMT is one of the interventions. IPD meta-analysis has been shown to be more reliable and valid than aggregate data meta-analysis, although this difference might also be attributed to the number of studies that can be used or the amount of data that can be utilized. Therefore, this project may identify important gaps in our knowledge with respect to prognostic factors of treatment effects. PROSPERO CRD42015025714