Rachel Court

Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes

Background Despite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents. Objective To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. Data sources MEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers. Inclusion criteria Randomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy. Methods Systematic review. Quality assessment used the Cochrane risk of bias score. Results Seven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by −0.54% (weighted mean differences (WMD), 95% CI −0.67 to −0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to −0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD −1.81 kg (95% CI −2.04 to −1.57), canagliflozin up to −2.3 kg compared to placebo). Limitations Long-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers. Conclusions Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed.

A systematic review of evidence on malignant spinal metastases: natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression

BACKGROUND Spinal metastases can lead to significant morbidity and reduction in quality of life due to spinal cord compression (SCC). Between 5% and 20% of patients with spinal metastases develop metastatic spinal cord compression during the course of their disease. An early study estimated average survival for patients with SCC to be between 3 and 7 months, with a 36% probability of survival to 12 months. An understanding of the natural history and early diagnosis of spinal metastases and prediction of collapse of the metastatic vertebrae are important. OBJECTIVES To undertake a systematic review to examine the natural history of metastatic spinal lesions and to identify patients at high risk of vertebral fracture and SCC. DATA SOURCES The search strategy covered the concepts of metastasis, the spine and adults. Searches were undertaken from inception to June 2011 in 13 electronic databases [MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials (CENTRAL); Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), HTA databases (NHS Centre for Reviews and Dissemination); Science Citation Index and Conference Proceedings (Web of Science); UK Clinical Research Network (UKCRN) Portfolio Database; Current Controlled Trials; ClinicalTrials.gov]. REVIEW METHODS Titles and abstracts of retrieved studies were assessed by two reviewers independently. Disagreement was resolved by consensus agreement. Full data were extracted independently by one reviewer. All included studies were reviewed by a second researcher with disagreements resolved by discussion. A quality assessment instrument was used to assess bias in six domains: study population, attrition, prognostic factor measurement, outcome measurement, confounding measurement and account, and analysis. Data were tabulated and discussed in a narrative review. Each tumour type was looked at separately. RESULTS In all, 2425 potentially relevant articles were identified, of which 31 met the inclusion criteria. No study examined natural history alone. Seventeen studies reported retrospective data, 10 were prospective studies, and three were other study designs. There was one systematic review. There were no randomised controlled trials (RCTs). Approximately 5782 participants were included. Sample sizes ranged from 41 to 859. The age of participants ranged between 7 and 92 years. Types of cancers reported on were lung alone (n= 3), prostate alone (n= 6), breast alone (n= 7), mixed cancers (n= 13) and unclear (n= 1). A total of 93 prognostic factors were identified as potentially significant in predicting risk of SCC or collapse. Overall findings indicated that the more spinal metastases present and the longer a patient was at risk, the greater the reported likelihood of development of SCC and collapse. There was an increased risk of developing SCC if a cancer had already spread to the bones. In the prostate cancer studies, tumour grade, metastatic load and time on hormone therapy were associated with increased risk of SCC. In one study, risk of SCC before death was 24%, and 2.37 times greater with a Gleason score ≥ 7 than with a score of < 7 (p= 0.003). Other research found that patients with six or more bone lesions were at greater risk of SCC than those with fewer than six lesions [odds ratio (OR) 2.9, 95% confidence interval (CI) 1.012 to 8.35, p= 0.047]. For breast cancer patients who received a computerised tomography (CT) scan for suspected SCC, multiple logistic regression in one study identified four independent variables predictive of a positive test: bone metastases ≥ 2 years (OR 3.0 95% CI 1.2 to 7.6; p= 0.02); metastatic disease at initial diagnosis (OR 3.4, 95% CI 1.0 to 11.4; p= 0.05); objective weakness (OR 3.8, 95% CI 1.5 to 9.5; p= 0.005); and vertebral compression fracture on spine radiograph (OR 2.6, 95% CI 1.0 to 6.5; p= 0.05). A further study on mixed cancers, among patients who received surgery for SCC, reported that vertebral body compression fractures were associated with presurgery chemotherapy (OR 2.283, 95% CI 1.064 to 4.898; p= 0.03), cancer type [primary breast cancer (OR 4.179, 95% CI 1.457 to 11.983; p= 0.008)], thoracic involvement (OR 3.505, 95% CI 1.343 to 9.143; p= 0.01) and anterior cord compression (OR 3.213, 95% CI 1.416 to 7.293; p= 0.005). LIMITATIONS Many of the included studies provided limited information about patient populations and selection criteria and they varied in methodological quality, rigour and transparency. Several studies identified type of cancer (e.g. breast, lung or prostate cancer) as a significant factor in predicting SCC, but it remains difficult to determine the risk differential partly because of residual bias. Consideration of quantitative results from the studies does not easily allow generation of a coherent numerical summary, studies were heterogeneous especially with regard to population, results were not consistent between studies, and study results almost universally lacked corroboration from other independent studies. CONCLUSION No studies were found which examined natural history. Overall burden of metastatic disease, confirmed metastatic bone involvement and immediate symptomatology suggestive of spinal column involvement are already well known as factors for metastatic SCC, vertebral collapse or progression of vertebral collapse. Although we identified a large number of additional possible prognostic factors, those which currently offer the most potential are unclear. Current clinical consensus favours magnetic resonance imaging and CT imaging modalities for the investigation of SCC and vertebral fracture. Future research should concentrate on: (1) prospective randomised designs to establish clinical and quality-of-life outcomes and cost-effectiveness of identification and treatment of patients at high risk of vertebral collapse and SCC; (2) Service Delivery and Organisation research on magnetic resonance imaging (MRI) scans and scanning (in tandem with research studies on use of MRI to monitor progression) in order to understand best methods for maximising use of MRI scanners; and (3) investigation of prognostic algorithms to calculate probability of a specified event using high-quality prospective studies, involving defined populations, randomly selected and clearly identified samples, and with blinding of investigators. FUNDING This report was commissioned by the National Institute for Health Research Health Technology Assessment Programme NIHR HTA Programme as project number HTA 10/91/01.

Do not attempt cardiopulmonary resuscitation (DNACPR) orders: a systematic review of the barriers and facilitators of decision-making and implementation.

UNLABELLED Most people who die in hospital do so with a DNACPR order in place, these orders are the focus of considerable debate. AIM To identify factors, facilitators and barriers involved in DNACPR decision-making and implementation. METHODS All study designs and interventions were eligible for inclusion. Studies were appraised guided by CASP tools. A qualitative analysis was undertaken. DATA SOURCES Included electronic databases: Medline, Embase, ASSIA, Cochrane library, CINAHL, PsycINFO, Web of Science, the Kings Fund Library and scanning reference lists of included studies. RESULTS Four key themes were identified: Considering the decision - by senior physicians, nursing staff, patients and relatives. Key triggers included older age, co-morbidities, adverse prognostic factors, quality of life and the likelihood of success of CPR. Discussing the decision - levels, and combinations, of physician and nursing skills, patient understanding and family involvement produced various outcomes. Implementing the decision - the lack of clear documentation resulted in a breakdown in communications within health teams. Staff knowledge and support of guidelines and local policies varied. Consequences of a DNACPR decision - inadequate understanding by staff resulted in suboptimal care, and incorrect withdrawal of treatment. CONCLUSION Significant variability was identified in DNACPR decision-making and implementation. The evidence base is weak but the absence of evidence does not indicate an absence of good practice. Issues are complex, and dependent on a number of factors. Misunderstandings and poor discussions can be overcome such as with an overall care plan to facilitate discussions and reduce negative impact of DNACPR orders on aspects of patient care.

Total hip replacement and surface replacement for the treatment of pain and disability resulting from end-stage arthritis of the hip (review of technology appraisal guidance 2 and 44): systematic review and economic evaluation

BACKGROUND Total hip replacement (THR) involves the replacement of a damaged hip joint with an artificial hip prosthesis. Resurfacing arthroplasty (RS) involves replacement of the joint surface of the femoral head with a metal surface covering. OBJECTIVES To undertake clinical effectiveness and cost-effectiveness analysis of different types of THR and RS for the treatment of pain and disability in people with end-stage arthritis of the hip, in particular to compare the clinical effectiveness and cost-effectiveness of (1) different types of primary THR and RS for people in whom both procedures are suitable and (2) different types of primary THR for people who are not suitable for hip RS. DATA SOURCES Electronic databases including MEDLINE, EMBASE, The Cochrane Library, Current Controlled Trials and UK Clinical Research Network (UKCRN) Portfolio Database were searched in December 2012, with searches limited to publications from 2008 and sample sizes of ≥ 100 participants. Reference lists and websites of manufacturers and professional organisations were also screened. REVIEW METHODS Systematic reviews of the literature were undertaken to appraise the clinical effectiveness and cost-effectiveness of different types of THR and RS for people with end-stage arthritis of the hip. Included randomised controlled trials (RCTs) and systematic reviews were data extracted and risk of bias and methodological quality were independently assessed by two reviewers using the Cochrane Collaboration risk of bias tool and the Assessment of Multiple Systematic Reviews (AMSTAR) tool. A Markov multistate model was developed for the economic evaluation of the technologies. Sensitivity analyses stratified by sex and controlled for age were carried out to assess the robustness of the results. RESULTS A total of 2469 records were screened of which 37 were included, representing 16 RCTs and eight systematic reviews. The mean post-THR Harris Hip Score measured at different follow-up times (from 6 months to 10 years) did not differ between THR groups, including between cross-linked polyethylene and traditional polyethylene cup liners (pooled mean difference 2.29, 95% confidence interval -0.88 to 5.45). Five systematic reviews reported evidence on different types of THR (cemented vs. cementless cup fixation and implant articulation materials) but these reviews were inconclusive. Eleven cost-effectiveness studies were included; four provided relevant cost and utility data for the model. Thirty registry studies were included, with no studies reporting better implant survival for RS than for all types of THR. For all analyses, mean costs for RS were higher than those for THR and mean quality-adjusted life-years (QALYs) were lower. The incremental cost-effectiveness ratio for RS was dominated by THR, that is, THR was cheaper and more effective than RS (for a lifetime horizon in the base-case analysis, the incremental cost of RS was £11,284 and the incremental QALYs were -0.0879). For all age and sex groups RS remained clearly dominated by THR. Cost-effectiveness acceptability curves showed that, for all patients, THR was almost 100% cost-effective at any willingness-to-pay level. There were age and sex differences in the populations with different types of THR and variations in revision rates (from 1.6% to 3.5% at 9 years). For the base-case analysis, for all age and sex groups and a lifetime horizon, mean costs for category E (cemented components with a polyethylene-on-ceramic articulation) were slightly lower and mean QALYs for category E were slightly higher than those for all other THR categories in both deterministic and probabilistic analyses. Hence, category E dominated the other four categories. Sensitivity analysis using an age- and sex-adjusted log-normal model demonstrated that, over a lifetime horizon and at a willingness-to-pay threshold of £20,000 per QALY, categories A and E were equally likely (50%) to be cost-effective. LIMITATIONS A large proportion of the included studies were inconclusive because of poor reporting, missing data, inconsistent results and/or great uncertainty in the treatment effect estimates. This warrants cautious interpretation of the findings. The evidence on complications was scarce, which may be because of the absence or rarity of these events or because of under-reporting. The poor reporting meant that it was not possible to explore contextual factors that might have influenced study results and also reduced the applicability of the findings to routine clinical practice in the UK. The scope of the review was limited to evidence published in English in 2008 or later, which could be interpreted as a weakness; however, systematic reviews would provide summary evidence for studies published before 2008. CONCLUSIONS Compared with THR, revision rates for RS were higher, mean costs for RS were higher and mean QALYs gained were lower; RS was dominated by THR. Similar results were obtained in the deterministic and probabilistic analyses and for all age and sex groups THR was almost 100% cost-effective at any willingness-to-pay level. Revision rates for all types of THR were low. Category A THR (cemented components with a polyethylene-on-metal articulation) was more cost-effective for older age groups. However, across all age-sex groups combined, the mean cost for category E THR (cemented components with a polyethylene-on-ceramic articulation) was slightly lower and the mean QALYs gained were slightly higher. Category E therefore dominated the other four categories. Certain types of THR appeared to confer some benefit, including larger femoral head sizes, use of a cemented cup, use of a cross-linked polyethylene cup liner and a ceramic-on-ceramic as opposed to a metal-on-polyethylene articulation. Further RCTs with long-term follow-up are needed. STUDY REGISTRATION This study is registered as PROSPERO CRD42013003924. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Cost-Effectiveness of Manual Therapy for the Management of Musculoskeletal Conditions: A Systematic Review and Narrative Synthesis of Evidence From Randomized Controlled Trials

OBJECTIVES The purpose of this study was to systematically review trial-based economic evaluations of manual therapy relative to other alternative interventions used for the management of musculoskeletal conditions. METHODS A comprehensive literature search was undertaken in major medical, health-related, science and health economic electronic databases. RESULTS Twenty-five publications were included (11 trial-based economic evaluations). The studies compared cost-effectiveness and/or cost-utility of manual therapy interventions to other treatment alternatives in reducing pain (spinal, shoulder, ankle). Manual therapy techniques (e.g., osteopathic spinal manipulation, physiotherapy manipulation and mobilization techniques, and chiropractic manipulation with or without other treatments) were more cost-effective than usual general practitioner (GP) care alone or with exercise, spinal stabilization, GP advice, advice to remain active, or brief pain management for improving low back and shoulder pain/disability. Chiropractic manipulation was found to be less costly and more effective than alternative treatment compared with either physiotherapy or GP care in improving neck pain. CONCLUSIONS Preliminary evidence from this review shows some economic advantage of manual therapy relative to other interventions used for the management of musculoskeletal conditions, indicating that some manual therapy techniques may be more cost-effective than usual GP care, spinal stabilization, GP advice, advice to remain active, or brief pain management for improving low back and shoulder pain/disability. However, at present, there is a paucity of evidence on the cost-effectiveness and/or cost-utility evaluations for manual therapy interventions. Further improvements in the methodological conduct and reporting quality of economic evaluations of manual therapy are warranted in order to facilitate adequate evidence-based decisions among policy makers, health care practitioners, and patients.

Total Hip Replacement for the Treatment of End Stage Arthritis of the Hip: A Systematic Review and Meta-Analysis

Background Evolvements in the design, fixation methods, size, and bearing surface of implants for total hip replacement (THR) have led to a variety of options for healthcare professionals to consider. The need to determine the most optimal combinations of THR implant is warranted. This systematic review evaluated the clinical effectiveness of different types of THR used for the treatment of end stage arthritis of the hip. Methods A comprehensive literature search was undertaken in major health databases. Randomised controlled trials (RCTs) and systematic reviews published from 2008 onwards comparing different types of primary THR in patients with end stage arthritis of the hip were included. Results Fourteen RCTs and five systematic reviews were included. Patients experienced significant post-THR improvements in Harris Hip scores, but this did not differ between impact types. There was a reduced risk of implant dislocation after receiving a larger femoral head size (36 mm vs. 28 mm; RR = 0.17, 95% CI: 0.04, 0.78) or cemented cup (vs. cementless cup; pooled odds ratio: 0.34, 95% CI: 0.13, 0.89). Recipients of cross-linked vs. conventional polyethylene cup liners experienced reduced femoral head penetration and revision. There was no impact of femoral stem fixation and cup shell design on implant survival rates. Evidence on mortality and complications (aseptic loosening, femoral fracture) was inconclusive. Conclusions The majority of evidence was inconclusive due to poor reporting, missing data, or uncertainty in treatment estimates. The findings warrant cautious interpretation given the risk of bias (blinding, attrition), methodological limitations (small sample size, low event counts, short follow-up), and poor reporting. Long-term pragmatic RCTs are needed to allow for more definitive conclusions. Authors are encouraged to specify the minimal clinically important difference and power calculation for their primary outcome(s) as well CONSORT, PRISMA and STROBE guidelines to ensure better reporting and more reliable production and assessment of evidence.

Belimumab: a technological advance for systemic lupus erythematosus patients? Report of a systematic review and meta-analysis

Objectives To undertake a systematic review and meta-analysis to investigate clinical effectiveness of belimumab for patients with systemic lupus erythematosus (SLE) and antinuclear and/or anti-double-stranded DNA (dsDNA) autoantibodies. Methods We searched eight electronic databases and reference lists for randomised controlled trials (RCTs) of belimumab against placebo or best supportive care. Quality assessment and random effects meta-analysis were undertaken. Design A meta-analysis of RCTs. Participants 2133 SLE patients. Primary and secondary outcome measures SLE Responder Index (SRI) at week 52. Results Three double-blind placebo-controlled RCTs (L02, BLISS-52 BLISS-76) investigated 2133 SLE patients. BLISS-52 and BLISS-76 trials recruited patients with antinuclear and/or anti-dsDNA autoantibodies and demonstrated belimumab effectiveness for the SRI at week 52. Ethnicity and geographical location of participants varied considerably between BLISS trials. Although tests for statistical heterogeneity were negative, BLISS-52 results were systematically more favourable for all measured outcomes. Meta-analysis of pooled 52-week SRI BLISS results showed benefit for belimumab (OR 1.63, 95% CI 1.27 to 2.09). By week 76, the primary SRI outcome in BLISS-76 was not statistically significant (OR 1.31, 95% CI 0.919 to 1.855).

Treatments for macular oedema following central retinal vein occlusion:systematic review

Objectives To review systematically the randomised controlled trial (RCT) evidence for treatment of macular oedema due to central retinal vein occlusion (CRVO). Data sources MEDLINE, EMBASE, CDSR, DARE, HTA, NHSEED, CENTRAL and meeting abstracts (January 2005 to March 2013). Study eligibility criteria, participants and interventions RCTs with at least 12 months of follow-up assessing pharmacological treatments for CRVO were included with no language restrictions. Study appraisal and synthesis methods 2 authors screened titles and abstracts and conducted data extracted and Cochrane risk of bias assessment. Meta-analysis was not possible due to lack of comparable studies. Results 8 studies (35 articles, 1714 eyes) were included, assessing aflibercept (n=2), triamcinolone (n=2), bevacizumab (n=1), pegaptanib (n=1), dexamethasone (n=1) and ranibizumab (n=1). In general, bevacizumab, ranibizumab, aflibercept and triamcinolone resulted in clinically significant increases in the proportion of participants with an improvement in visual acuity of ≥15 letters, with 40–60% gaining ≥15 letters on active drugs, compared to 12–28% with sham. Results for pegaptanib and dexamethasone were mixed. Steroids were associated with cataract formation and increased intraocular pressure. No overall increase in adverse events was found with bevacizumab, ranibizumab, aflibercept or pegaptanib compared with control. Quality of life was poorly reported. All studies had a low or unclear risk of bias. Limitations All studies evaluated a relatively short primary follow-up (1 year or less). Most had an unmasked extension phase. There was no head-to-head evidence. The majority of participants included had non-ischaemic CRVO. Conclusions and implications of key findings Bevacizumab, ranibizumab, aflibercept and triamcinolone appear to be effective in treating macular oedema secondary to CRVO. Long-term data on effectiveness and safety are needed. Head-to-head trials and research to identify ‘responders’ is needed to help clinicians make the right choices for their patients. Research aimed to improve sight in people with ischaemic CRVO is required.

Accurate diagnosis of latent tuberculosis in children, people who are immunocompromised or at risk from immunosuppression and recent arrivals from countries with a high incidence of tuberculosis: systematic review and economic evaluation

BACKGROUND Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) [(Zopf 1883) Lehmann and Neumann 1896], is a major cause of morbidity and mortality. Nearly one-third of the worlds population is infected with MTB; TB has an annual incidence of 9 million new cases and each year causes 2 million deaths worldwide. OBJECTIVES To investigate the clinical effectiveness and cost-effectiveness of screening tests [interferon-gamma release assays (IGRAs) and tuberculin skin tests (TSTs)] in latent tuberculosis infection (LTBI) diagnosis to support National Institute for Health and Care Excellence (NICE) guideline development for three population groups: children, immunocompromised people and those who have recently arrived in the UK from high-incidence countries. All of these groups are at higher risk of progression from LTBI to active TB. DATA SOURCES Electronic databases including MEDLINE, EMBASE, The Cochrane Library and Current Controlled Trials were searched from December 2009 up to December 2014. REVIEW METHODS English-language studies evaluating the comparative effectiveness of commercially available tests used for identifying LTBI in children, immunocompromised people and recent arrivals to the UK were eligible. Interventions were IGRAs [QuantiFERON(®)-TB Gold (QFT-G), QuantiFERON(®)-TB Gold-In-Tube (QFT-GIT) (Cellestis/Qiagen, Carnegie, VA, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK)]. The comparator was TST 5 mm or 10 mm alone or with an IGRA. Two independent reviewers screened all identified records and undertook a quality assessment and data synthesis. A de novo model, structured in two stages, was developed to compare the cost-effectiveness of diagnostic strategies. RESULTS In total, 6687 records were screened, of which 53 unique studies were included (a further 37 studies were identified from a previous NICE guideline). The majority of the included studies compared the strength of association for the QFT-GIT/G IGRA with the TST (5 mm or 10 mm) in relation to the incidence of active TB or previous TB exposure. Ten studies reported evidence on decision-analytic models to determine the cost-effectiveness of IGRAs compared with the TST for LTBI diagnosis. In children, TST (≥ 5 mm) negative followed by QFT-GIT was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of £18,900 per quality-adjusted life-year (QALY) gained. In immunocompromised people, QFT-GIT negative followed by the TST (≥ 5 mm) was the most cost-effective strategy, with an ICER of approximately £18,700 per QALY gained. In those recently arrived from high TB incidence countries, the TST (≥ 5 mm) alone was less costly and more effective than TST (≥ 5 mm) positive followed by QFT-GIT or T-SPOT.TB or QFT-GIT alone. LIMITATIONS The limitations and scarcity of the evidence, variation in the exposure-based definitions of LTBI and heterogeneity in IGRA performance relative to TST limit the applicability of the review findings. CONCLUSIONS Given the current evidence, TST (≥ 5 mm) negative followed by QFT-GIT for children, QFT-GIT negative followed by TST (≥ 5 mm) for the immunocompromised population and TST (≥ 5 mm) for recent arrivals were the most cost-effective strategies for diagnosing LTBI that progresses to active TB. These results should be interpreted with caution given the limitations identified. The evidence available is limited and more high-quality research in this area is needed including studies on the inconsistent performance of tests in high-compared with low-incidence TB settings; the prospective assessment of progression to active TB for those at high risk; the relative benefits of two-compared with one-step testing with different tests; and improved classification of people at high and low risk for LTBI. STUDY REGISTRATION This study is registered as PROSPERO CRD42014009033. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Clinical effectiveness and cost-effectiveness of elemental nutrition for the maintenance of remission in Crohn’s disease: a systematic review and meta-analysis

BACKGROUND Although enteral nutrition has been shown to be a viable treatment option for the management of active Crohns disease (CD), the evidence regarding its clinical benefits compared with standard treatments (e.g. steroids) for maintaining remission in patients with CD has been inconsistent. If enteral nutrition was to be effective, the use of drugs such as steroids and immunosuppressive drugs could be reduced, thereby reducing the likelihood of adverse events associated with these medications. OBJECTIVES This systematic review aimed to assess the clinical effectiveness and cost-effectiveness of elemental nutrition (a type of enteral nutrition) for maintenance of remission in patients with CD. DATA SOURCES Major bibliographic databases (e.g. MEDLINE, EMBASE, Cochrane Database of Systematic Reviews) were searched from inception to August/September 2013. Searches were not limited by study design, language or publication date. Websites for relevant organisations and references of included studies were checked. METHODS Experimental randomised and non-randomised controlled trials (RCTs and nRCTs) reporting clinical effectiveness and cost-effectiveness of elemental nutrition in the maintenance of remission in patients with CD were eligible. Study selection, data extraction and risk of bias (RoB) assessment were performed independently. Risk ratios (RRs) and mean differences (MDs) were pooled using a random-effects model. Heterogeneity was assessed via forest plots, Cochrans Q and the I2 statistics. Overall, quality of evidence for each outcome was rated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS Eight studies (three RCTs and five nRCTs) were included in the review. RCTs indicated a significant benefit of elemental nutrition vs. no intervention (an unrestricted diet) in maintaining remission at 24 months [one RCT; RR 2.06, 95% confidence interval (CI) 1.00 to 4.43; very low-grade evidence] and preventing relapse at 12-24 months post baseline (two RCTs; pooled RR 0.57, 95% CI 0.38 to 0.84; I2 = 0%; high-grade evidence). Similarly, three nRCTs showed significant benefits of elemental nutrition over no intervention in maintaining remission at 12-48 months and preventing relapse at 12 months post baseline (MD 1.20 months, 95% CI 0.35 to 2.04 months). The incidence of mucosal healing was not significantly different in the intervention and control groups (RR 2.70, 95% CI 0.62 to 11.72). Adherence to an elemental nutrition regime was significantly worse than adherence to polymeric nutrition (RR 0.68, 95% CI 0.50 to 0.92) and, when compared with other active treatments (medications, polymeric nutrition or a combination), elemental nutrition yielded non-significant results with wide 95% CIs, rendering these results inconclusive. Complications and adverse events were too sparse to allow meaningful comparisons. None of the studies reported cost-effectiveness of elemental nutrition. Owing to scarcity of data, subgroup and sensitivity analyses could not be performed to explore methodological and clinical sources of heterogeneity. LIMITATIONS The findings warrant cautious interpretation given the limitations of the evidence in methodological quality (small samples, short follow-up) and the RoB in individual studies (lack of blinding, confounding). CONCLUSIONS Limited evidence indicates potential benefits of elemental nutrition against no intervention in the maintenance of remission and prevention of relapse in adult patients with CD. There was a lack or insufficient evidence on adverse events and complications. Future large and long-term randomised trials are warranted to draw more definitive conclusions regarding the effects of elemental nutrition in maintaining remission in CD. TRIAL REGISTRATION This study is registered as PROSPERO CRD42013005134. FUNDING The National Institute for Health Research Health Technology Assessment programme.