Comparative effectiveness of mRNA-1273 and BNT162b2 COVID-19 vaccines in immunocompromised individuals: a systematic review and meta-analysis using the GRADE framework.

Introduction: Despite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response after vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) vs BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework. Methods: The systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals ≥18 years of age; outcomes of interest were symptomatic, laboratory-confirmed SARS-CoV-2 infection, SARS-CoV-2 infection, severe SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Evidence was evaluated using the GRADE framework. Results: Overall, 17 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.75-0.97]; P=0.0151; I2 = 67.7%), severe SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.77-0.93]; P=0.0009; I2 = 0%), COVID-19-associated hospitalization (RR, 0.88 [95% CI, 0.79-0.97]; P<0.0001; I2 = 0%), and COVID-19-associated mortality (RR, 0.63 [95% CI, 0.44-0.90]; P=0.0119; I2 = 0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials. Based on nonrandomized studies, evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies. Conclusion: This GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2.

Diagnostic Models Combining Clinical Information, Ultrasound and Biochemical Markers for Ovarian Cancer: Cochrane Systematic Review and Meta-Analysis.

Background: Ovarian cancer (OC) is a diagnostic challenge, with the majority diagnosed at late stages. Existing systematic reviews of diagnostic models either use inappropriate meta-analytic methods or do not conduct statistical comparisons of models or stratify test performance by menopausal status. Methods: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, CDSR, DARE, Health Technology Assessment Database and SCI Science Citation Index, trials registers, conference proceedings from 1991 to June 2019. Cochrane collaboration review methods included QUADAS-2 quality assessment and meta-analysis using hierarchical modelling. RMI, ROMA or ADNEX at any test positivity threshold were investigated. Histology or clinical follow-up was the reference standard. We excluded screening studies, studies restricted to pregnancy, recurrent or metastatic OC. 2 × 2 diagnostic tables were extracted separately for pre- and post-menopausal women. Results: We included 58 studies (30,121 patients, 9061 cases of ovarian cancer). Prevalence of OC ranged from 16 to 55% in studies. For premenopausal women, ROMA at a threshold of 13.1 (+/−2) and ADNEX at a threshold of 10% demonstrated significantly higher sensitivity compared to RMI I at 200 (p < 0.0001) 77.8 (72.5, 82.4), 94.9 (92.5, 96.6), and 57.1% (50.6 to 63.4) but lower specificity (p < 0.002), 92.5 (90.0, 94.4), 84.3 (81.3, 86.8), and 78.2 (75.8, 80.4). For postmenopausal women, ROMA at a threshold of 27.7 (+/−2) and AdNEX at a threshold of 10% demonstrated significantly higher sensitivity compared to RMI I at a threshold of 200 (p < 0.001) 90.4 (87.4, 92.7), 97.6 (96.2, 98.5), and 78.7 (74.3, 82.5), specificity of ROMA was comparable, whilst ADneX was lower, 85.5 (81.3, 88.9), 81.3 (76.9, 85.0) (p = 0.155), compared to RMI 55.2 (51.2, 59.1) (p < 0.001). Conclusions: In pre-menopausal women, ROMA and ADNEX offer significantly higher sensitivity but significantly decreased specificity. In post-menopausal women, ROMA demonstrates significantly higher sensitivity and comparable specificity to RMI I, ADNEX has the highest sensitivity of all models, but with significantly reduced specificity. RMI I has poor sensitivity compared to ROMA or ADNEX. Choice between ROMA and ADNEX as a replacement test will depend on cost effectiveness and resource implications.

Menopausal status, ultrasound and biomarker tests in combination for the diagnosis of ovarian cancer in symptomatic women.

BACKGROUND: Ovarian cancer (OC) has the highest case fatality rate of all gynaecological cancers. Diagnostic delays are caused by non-specific symptoms. Existing systematic reviews have not comprehensively covered tests in current practice, not estimated accuracy separately in pre- and postmenopausal women, or used inappropriate meta-analytic methods. OBJECTIVES: To establish the accuracy of combinations of menopausal status, ultrasound scan (USS) and biomarkers for the diagnosis of ovarian cancer in pre- and postmenopausal women and compare the accuracy of different test combinations. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), five other databases and three trial registries from 1991 to 2015 and MEDLINE (Ovid) and Embase (Ovid) form June 2015 to June 2019. We also searched conference proceedings from the European Society of Gynaecological Oncology, International Gynecologic Cancer Society, American Society of Clinical Oncology and Society of Gynecologic Oncology, ZETOC and Conference Proceedings Citation Index (Web of Knowledge). We searched reference lists of included studies and published systematic reviews. SELECTION CRITERIA: We included cross-sectional diagnostic test accuracy studies evaluating single tests or comparing two or more tests, randomised trials comparing two or more tests, and studies validating multivariable models for the diagnosis of OC investigating test combinations, compared with a reference standard of histological confirmation or clinical follow-up in women with a pelvic mass (detected clinically or through USS) suspicious for OC. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality using QUADAS-2. We used the bivariate hierarchical model to indirectly compare tests at commonly reported thresholds in pre- and postmenopausal women separately. We indirectly compared tests across all thresholds and estimated sensitivity at fixed specificities of 80% and 90% by fitting hierarchical summary receiver operating characteristic (HSROC) models in pre- and postmenopausal women separately. MAIN RESULTS: We included 59 studies (32,059 women, 9545 cases of OC). Two tests evaluated the accuracy of a combination of menopausal status and USS findings (IOTA Logistic Regression Model 2 (LR2) and the Assessment of Different NEoplasias in the adneXa model (ADNEX)); one test evaluated the accuracy of a combination of menopausal status, USS findings and serum biomarker CA125 (Risk of Malignancy Index (RMI)); and one test evaluated the accuracy of a combination of menopausal status and two serum biomarkers (CA125 and HE4) (Risk of Ovarian Malignancy Algorithm (ROMA)). Most studies were at high or unclear risk of bias in participant, reference standard, and flow and timing domains. All studies were in hospital settings. Prevalence was 16% (RMI, ROMA), 22% (LR2) and 27% (ADNEX) in premenopausal women and 38% (RMI), 45% (ROMA), 52% (LR2) and 55% (ADNEX) in postmenopausal women. The prevalence of OC in the studies was considerably higher than would be expected in symptomatic women presenting in community-based settings, or in women referred from the community to hospital with a suspicion of OC. Studies were at high or unclear applicability because presenting features were not reported, or USS was performed by experienced ultrasonographers for RMI, LR2 and ADNEX. The higher sensitivity and lower specificity observed in postmenopausal compared to premenopausal women across all index tests and at all thresholds may reflect highly selected patient cohorts in the included studies. In premenopausal women, ROMA at a threshold of 13.1 (± 2), LR2 at a threshold to achieve a post-test probability of OC of 10% and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 77.4%, 95% CI 72.7% to 81.5%; LR2: 83.3%, 95% CI 74.7% to 89.5%; ADNEX: 95.5%, 95% CI 91.0% to 97.8%) compared to RMI (57.2%, 95% CI 50.3% to 63.8%). The specificity of ROMA and ADNEX were lower in premenopausal women (ROMA: 84.3%, 95% CI 81.2% to 87.0%; ADNEX: 77.8%, 95% CI 67.4% to 85.5%) compared to RMI 92.5% (95% CI 90.3% to 94.2%). The specificity of LR2 was comparable to RMI (90.4%, 95% CI 84.6% to 94.1%). In postmenopausal women, ROMA at a threshold of 27.7 (± 2), LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 90.3%, 95% CI 87.5% to 92.6%; LR2: 94.8%, 95% CI 92.3% to 96.6%; ADNEX: 97.6%, 95% CI 95.6% to 98.7%) compared to RMI (78.4%, 95% CI 74.6% to 81.7%). Specificity of ROMA at a threshold of 27.7 (± 2) (81.5, 95% CI 76.5% to 85.5%) was comparable to RMI (85.4%, 95% CI 82.0% to 88.2%), whereas for LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) specificity was lower (LR2: 60.6%, 95% CI 50.5% to 69.9%; ADNEX: 55.0%, 95% CI 42.8% to 66.6%). AUTHORS' CONCLUSIONS: In specialist healthcare settings in both premenopausal and postmenopausal women, RMI has poor sensitivity. In premenopausal women, ROMA, LR2 and ADNEX offer better sensitivity (fewer missed cancers), but for ROMA and ADNEX this is off-set by a decrease in specificity and increase in false positives. In postmenopausal women, ROMA demonstrates a higher sensitivity and comparable specificity to RMI. ADNEX has the highest sensitivity in postmenopausal women, but reduced specificity. The prevalence of OC in included studies is representative of a highly selected referred population, rather than a population in whom referral is being considered. The comparative accuracy of tests observed here may not be transferable to non-specialist settings. Ultimately health systems need to balance accuracy and resource implications to identify the most suitable test.

Contrast-enhanced ultrasound and/or colour duplex ultrasound for surveillance after endovascular abdominal aortic aneurysm repair: a systematic review and economic evaluation.

BACKGROUND: Endovascular abdominal aortic aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA) is less invasive than open surgery, but may be associated with important complications. Patients receiving EVAR require long-term surveillance to detect abnormalities and direct treatments. Computed tomography angiography (CTA) has been the most common imaging modality adopted for EVAR surveillance, but it is associated with repeated radiation exposure and the risk of contrast-related nephropathy. Colour duplex ultrasound (CDU) and, more recently, contrast-enhanced ultrasound (CEU) have been suggested as possible, safer, alternatives to CTA. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of imaging strategies, using either CDU or CEU alone or in conjunction with plain radiography, compared with CTA for EVAR surveillance. DATA SOURCES: Major electronic databases were searched, including MEDLINE, EMBASE, Science Citation Index, Scopus' Articles-in-Press, Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database from 1996 onwards. We also searched for relevant ongoing studies and conference proceedings. The final searches were undertaken in September 2016. METHODS: We conducted a systematic review of randomised controlled trials and cohort studies of patients with AAAs who were receiving surveillance using CTA, CDU and CEU with or without plain radiography. Three reviewers were involved in the study selection, data extraction and risk-of-bias assessment. We developed a Markov model based on five surveillance strategies: (1) annual CTA; (2) annual CDU; (3) annual CEU; (4) CDU together with CTA at 1 year, followed by CDU on an annual basis; and (5) CEU together with CTA at 1 year, followed by CEU on an annual basis. All of these strategies also considered plain radiography on an annual basis. RESULTS: We identified two non-randomised comparative studies and 25 cohort studies of interventions, and nine systematic reviews of diagnostic accuracy. Overall, the proportion of patients who required reintervention ranged from 1.1% (mean follow-up of 24 months) to 23.8% (mean follow-up of 32 months). Reintervention was mainly required for patients with thrombosis and types I-III endoleaks. All-cause mortality ranged from 2.7% (mean follow-up of 24 months) to 42% (mean follow-up of 54.8 months). Aneurysm-related mortality occurred in < 1% of the participants. Strategies based on early and mid-term CTA and/or CDU and long-term CDU surveillance were broadly comparable with those based on a combination of CTA and CDU throughout the follow-up period in terms of clinical complications, reinterventions and mortality. The economic evaluation showed that a CDU-based strategy generated lower expected costs and higher quality-adjusted life-year (QALYs) than a CTA-based strategy and has a 63% probability of being cost-effective at a £30,000 willingness-to-pay-per-QALY threshold. A CEU-based strategy generated more QALYs, but at higher costs, and became cost-effective only for high-risk patient groups. LIMITATIONS: Most studies were rated as being at a high or moderate risk of bias. No studies compared CDU with CEU. Substantial clinical heterogeneity precluded a formal synthesis of results. The economic model was hindered by a lack of suitable data. CONCLUSIONS: Current surveillance practice is very heterogeneous. CDU may be a safe and cost-effective alternative to CTA, with CTA being reserved for abnormal/inconclusive CDU cases. FUTURE WORK: Research is needed to validate the safety of modified, more-targeted surveillance protocols based on the use of CDU and CEU. The role of radiography for surveillance after EVAR requires clarification. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016036475. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis.

Objective To assess whether weight loss interventions for adults with obesity affect all cause, cardiovascular, and cancer mortality, cardiovascular disease, cancer, and body weight.Design Systematic review and meta-analysis of randomised controlled trials (RCTs) using random effects, estimating risk ratios, and mean differences. Heterogeneity investigated using Cochran's Q and I2 statistics. Quality of evidence assessed by GRADE criteria.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, and full texts in our trials' registry for data not evident in databases. Authors were contacted for unpublished data.Eligibility criteria for selecting studies RCTs of dietary interventions targeting weight loss, with or without exercise advice or programmes, for adults with obesity and follow-up ≥1 year.Results 54 RCTs with 30 206 participants were identified. All but one trial evaluated low fat, weight reducing diets. For the primary outcome, high quality evidence showed that weight loss interventions decrease all cause mortality (34 trials, 685 events; risk ratio 0.82, 95% confidence interval 0.71 to 0.95), with six fewer deaths per 1000 participants (95% confidence interval two to 10). For other primary outcomes moderate quality evidence showed an effect on cardiovascular mortality (eight trials, 134 events; risk ratio 0.93, 95% confidence interval 0.67 to 1.31), and very low quality evidence showed an effect on cancer mortality (eight trials, 34 events; risk ratio 0.58, 95% confidence interval 0.30 to 1.11). Twenty four trials (15 176 participants) reported high quality evidence on participants developing new cardiovascular events (1043 events; risk ratio 0.93, 95% confidence interval 0.83 to 1.04). Nineteen trials (6330 participants) provided very low quality evidence on participants developing new cancers (103 events; risk ratio 0.92, 95% confidence interval 0.63 to 1.36).Conclusions Weight reducing diets, usually low in fat and saturated fat, with or without exercise advice or programmes, may reduce premature all cause mortality in adults with obesity.Systematic review registration PROSPERO CRD42016033217.

Relative effectiveness of robot-assisted and standard laparoscopic prostatectomy as alternatives to open radical prostatectomy for treatment of localised prostate cancer: a systematic review and mixed treatment comparison meta-analysis.

OBJECTIVE: To compare the effectiveness of robot-assisted and standard laparoscopic prostatectomy. METHODS: A care pathway was described. We performed a systematic literature review based on a search of Medline, Medline in Process, Embase, Biosis, Science Citation Index, Cochrane Controlled Trials Register, Current Controlled Trials, Clinical Trials, WHO International Clinical Trials Registry and NIH Reporter, the Health Technology Assessment databases, the Database of Abstracts of Reviews of Effects, and relevant conference abstracts up to 31st October 2010). Additionally, reference lists were scanned, an expert panel consulted, and websites of manufacturers, professional organisations, and regulatory bodies were checked. We selected randomised controlled trials (RCTs) and non-randomised comparative studies, published after 1st January 1995, including men with localised prostate cancer undergoing robot-assisted or laparoscopic prostatectomy compared with the other procedure or with open prostatectomy. Studies where at least 90% of included men had clinical tumour stages T1 to T2 and which reported at least one of our specified outcomes were eligible for inclusion. A mixed-treatment comparison meta-analysis was performed to generate comparative statistics on specified outcomes. RESULTS: We included data from 19 064 men across one RCT and 57 non-randomised comparative reports. Robotic prostatectomy had a lower risk of major intra-operative harms such as organ injury [0.4% robotic vs 2.9% laparoscopic], odds ratio ([OR] {95% credible interval [CrI]} 0.16 [0.03 to 0.76]), and a lower rate of surgical margins positive for cancer [17.6% robotic vs 23.6% laparoscopic], OR [95% CrI] 0.69 [0.51 to 0.96]). There was no evidence of a difference in the proportion of men with urinary incontinence at 12 months (OR [95% CrI] 0.55 [0.09 to 2.84]). There were insufficient data on sexual dysfunction. Surgeon learning rates for the procedures did not differ, although data were limited. CONCLUSIONS: Men undergoing robotic prostatectomy appear to have reduced surgical morbidity, and a lower risk of a positive surgical margin, which may reduce rates of cancer recurrence and the need for further treatment, but considerable uncertainty surrounds these results. We found no evidence that men undergoing robotic prostatectomy are disadvantaged in terms of early outcomes. We were unable to determine longer-term relative effectiveness.

Screening for major diseases in community pharmacies: a systematic review.

OBJECTIVES: The aim of this systematic review was to assess the published evidence about the feasibility and acceptability of community pharmacy-based screening for major diseases. METHOD: Studies published between January 1990 and August 2012 involving community pharmacy-based screening interventions, published in the English language, were identified from electronic databases. Reference lists of included studies were also searched. KEY FINDINGS: Fifty studies (one randomised controlled trial, two cluster randomised studies, five non-randomised comparative studies and 42 uncontrolled studies) were included. The quality of most of these was assessed as poor. Screening was mostly opportunistic and screening tools included questionnaires or risk assessment forms, medical equipment to make physiological measurements, or a combination of both. Few studies assessed the accuracy of pharmacy-based screening tools. More than half of the screening interventions included an element of patient education. The proportion of screened individuals, identified with disease risk factors or the disease itself, ranged from 4% to 89%. Only 10 studies reported any economic information. Where assessed, patient satisfaction with pharmacy-based screening was high, but individuals who screened positive often did not follow pharmacist advice to seek further medical help. CONCLUSION: Available evidence suggests that screening for some diseases in community pharmacies is feasible. More studies are needed to compare effectiveness and cost-effectiveness of pharmacy-based screening with screening by other providers. Strategies to improve screening participants' adherence to pharmacist advice also need to be explored. This systematic review will help to inform future studies wishing to develop community pharmacy-based screening interventions.

Denosumab for treatment of bone metastases secondary to solid tumours: systematic review and network meta-analysis.

AIM: To evaluate the evidence for denosumab for the treatment of bone metastases secondary to solid tumours and, using a network meta-analysis, indirectly compare denosumab with bisphosphonates and best supportive care. DATA SOURCES: MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), Cochrane Library (all sections) (issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011) and additional meeting abstracts (2010 and 2011) were searched. STUDY ELIGIBILITY, PARTICIPANTS AND INTERVENTIONS: Only randomised controlled trials assessing denosumab, bisphosphonates or best supportive care in patients with bone metastases from any solid tumour were included. SYNTHESIS: Direct evidence comparing denosumab and zoledronic acid was assessed for breast cancer, prostate cancer and other solid tumours. Denosumab was compared with pamidronate and best supportive care through a network meta-analysis for each tumour type. The primary outcomes were time to first skeletal related event (SRE) and time to first and subsequent SRE. Secondary outcomes were skeletal morbidity rate, pain, quality of life (QoL) and overall survival. RESULTS: Denosumab was found to be more effective in delaying the time to first SRE and reducing the risk of first and subsequent SRE compared to zoledronic acid, placebo and pamidronate. In breast and prostate cancer, denosumab was effective in reducing skeletal morbidity rate compared with placebo. The lack of published data on pain and QoL meant that firm conclusions could not be made. Denosumab did not appear to have an affect on overall survival. LIMITATIONS: Network meta-analyses are subject to uncertainties and potential biases. CONCLUSIONS: Denosumab is effective in preventing SRE, but the effect on pain and QoL is unclear.

NICE guidance: a comparative study of the introduction of the single technology appraisal process and comparison with guidance from Scottish Medicines Consortium.

Objectives To compare the timelines and recommendations of the Scottish Medicines Consortium (SMC) and National Institute of Health and Clinical Excellence (NICE), in particular since the single technology assessment (STA) process was introduced in 2005. Design Comparative study of drug appraisals published by NICE and SMC. Setting NICE and SMC. Participants All drugs appraised by SMC and NICE, from establishment of each organisation until August 2010, were included. Data were gathered from published reports on the NICE website, SMC annual reports and European Medicines Agency website. Primary and secondary outcome measures Primary outcome was time from marketing authorisation until publication of first guidance. The final outcome for each drug was documented. Drug appraisals by NICE (before and after the introduction of the STA process) and SMC were compared. Results NICE and SMC appraised 140 drugs, 415 were appraised by SMC alone and 102 by NICE alone. NICE recommended, with or without restriction, 90% of drugs and SMC 80%. SMC published guidance more quickly than NICE (median 7.4 compared with 21.4 months). Overall, the STA process reduced the average time to publication compared with multiple technology assessments (median 16.1 compared with 22.8 months). However, for cancer medications, the STA process took longer than multiple technology assessment (25.2 compared with 20.0 months). Conclusions Proportions of drugs recommended for NHS use by SMC and NICE are similar. SMC publishes guidance more quickly than NICE. The STA process has improved the time to publication but not for cancer drugs. The lengthier time for NICE guidance is partly due to measures to provide transparency and the widespread consultation during the NICE process.

Systematic review of escalated imatinib doses compared with sunitinib or best supportive care, for the treatment of people with unresectable/metastatic gastrointestinal stromal tumours whose disease has progressed on the standard imatinib dose.

INTRODUCTION: We conducted a systematic review of evidence on the effectiveness of imatinib at escalated doses of 600 mg/day or 800 mg/day for treatment of adults with unresectable or metastatic gastrointestinal stromal tumours (GIST), following progression on imatinib at the 400 mg/day dose, compared with sunitinib and/or 'best supportive care'. METHODS: Electronic searches were undertaken to identify relevant randomised controlled trials (RCTs), non-randomised studies, and case series reporting outcome data on survival, quality of life or adverse events. Titles and abstracts were screened by two reviewers and full text reports of potentially relevant studies assessed for inclusion. Included studies were quality assessed by two reviewers and data were extracted. Five studies reported data on the relevant population and were included. RESULTS AND DISCUSSION: Median overall survival for imatinib (800 mg/day) and sunitinib both were less than 2 years. Around 25% of patients required either an imatinib dose delay or reduction. Approximately one-third of patients receiving dose escalated imatinib (either dose) showed either response or stable disease. Amongst those responding to the escalated 800 mg/day dose, median progression-free survival was over 25 months. The statistical likelihood of response may depend on exon mutational status. There were few data and those that were available were potentially biased, due to their non-randomised nature. Further data are needed to justify international guideline recommendations on imatinib dose escalation. CONCLUSION: A prospective audit of management and outcomes for unresectable GIST patients treated with dose escalation upon progression at 400 mg/day may be appropriate as an RCT may be unfeasible.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a long term condition that occurs as a result of damage to the kidneys. Early recognition of CKD is becoming increasingly common due to widespread laboratory estimated glomerular filtration rate (eGFR) reporting, raised clinical awareness, and international adoption of Kidney Disease Outcomes Quality Initiative (K/DOQI) classification. Early recognition and management of CKD affords the opportunity not only to prepare for progressive kidney impairment and impending renal replacement therapy, but also for intervening to reduce the risk of progression and cardiovascular disease. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are two classes of antihypertensive drugs that act on the renin-angiotensin-aldosterone system. Beneficial effects of ACEi and ARB on renal outcomes and survival in people with a wide range of severity of renal impairment have been reported; however, their effectiveness in the subgroup of people with early CKD (stage 1 to 3) is less certain. OBJECTIVES: This review aimed to evaluate the benefits and harms of ACEi and ARB or both in the management of people with early (stage 1 to 3) CKD who do not have diabetes mellitus. SEARCH STRATEGY: In March 2010 we searched The Cochrane Library, including The Cochrane Renal Group's specialised register and The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. Reference lists of review articles and relevant studies were also checked. The search was conducted using the optimally sensitive strategy developed by the Cochrane Collaboration for the identification of randomised controlled trials (RCTs) with input from an expert in trial search strategy. SELECTION CRITERIA: All RCTs reporting the effect of ACEi or ARB in people with early (stage 1 to 3) CKD who did not have diabetes mellitus were selected for inclusion. Only studies of at least four weeks duration were selected. Authors, working in teams of two, independently assessed the retrieved titles and abstracts, and whenever necessary the full text of these studies were screened to determine which studies satisfied the inclusion criteria. DATA COLLECTION AND ANALYSIS: Data extraction was carried out by two authors, independently, using a standard data extraction form and cross checked by two other authors. Methodological quality of included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross checked by another author. When more than one study reported similar outcomes, data were pooled using the random-effects model, but a fixed-effect model was also analysed to ensure the robustness of the model chosen and to check susceptibility to outliers. Heterogeneity was analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test. Where data permitted, subgroup analysis was used to explore possible sources of heterogeneity. The quality of the evidence was analysed. MAIN RESULTS: Four RCTs enrolling 2177 participants met our inclusion criteria. Of these, three compared ACEi with placebo and one compared ACEi with ARB. Two studies had an overall low risk of bias, and the other two were considered to be at moderate to high risk of bias. Low to moderate quality of evidence (from two studies representing 1906 patients) suggested that ACEi had no impact on all-cause mortality (RR 1.80, 95% CI 0.17 to 19.27, P = 0.63) or cardiovascular events (RR 0.87, 95% CI 0.66 to 1.14, P = 0.31) in people with stage 3 CKD. For all-cause mortality, there was substantial heterogeneity in the results. One study (quality assessment: low risk of bias) reported no difference in the risk of end-stage kidney disease in those with an eGFR > 45 mL/min/1.74 m² treated with ACEi versus placebo (RR 1.00, 95% CI 0.09 to 1.11, P = 0.99). The (high risk of bias) study that compared ACEi with ARB reported little difference in effect between the treatments when urinary protein, blood pressure or creatinine clearance were compared. No published studies comparing ARB with placebo or ACEi and ARB with placebo were identified. AUTHORS' CONCLUSIONS: Our review demonstrated that there is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with stage 1 to 3 CKD who do not have diabetes mellitus. We have identified an area of significant uncertainty for a group of patients who account for most of those labelled as having CKD.