Tramadol versus placebo for chronic pain: a systematic review with meta-analysis and trial sequential analysis.

ObjectivesTo assess the beneficial and harmful effects of adding ivabradine to usual care in participants with heart failure.DesignA systematic review with meta-analysis and trial sequential analysis.Eligibility criteriaRandomised clinical trials comparing...

Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as the basic pain treatment regimen for most surgeries. Glucocorticoids have well-known anti-inflammatory and anti-emetic properties and may also demonstrate analgesic effects. We assessed benefit and harm of adding glucocorticoids to a combination of paracetamol and NSAIDs for post-operative pain management. We searched Embase, Medline and CENTRAL for randomised clinical trials investigating the addition of glucocorticoids versus placebo/no intervention to paracetamol and an NSAID in adults undergoing any type of surgery. We assessed three primary outcomes: cumulative opioid consumption at 24 h postoperatively, serious adverse events and pain at rest at 24 h postoperatively. We performed meta-analysis and trial sequential analysis (TSA), assessed risk of bias using the Risk of Bias 2 tool and used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate the certainty of the evidence. We identified 12 relevant trials of which nine trials randomising 804 participants were included in quantitative analysis. When added to paracetamol and NSAIDs, we found no evidence of a difference of glucocorticoids versus placebo/no intervention in cumulative opioid consumption at 24 h postoperatively (mean difference [MD] -0.28, TSA-adjusted 95% confidence interval [CI] -1.90 to 1.33, p=.68, moderate certainty of evidence), serious adverse events (risk ratio (RR) 0.99, TSA-adjusted 95% CI 0.27-3.63, p=.93, very low certainty of evidence) or pain on the Numeric Rating Scale at 24 h postoperatively (MD -0.39, TSA-adjusted 95% CI -0.84 to 0.17, p=.10, moderate certainty of evidence). All outcomes were assessed to be at high risk of bias and TSA showed that we had insufficient information for most outcomes. Glucocorticoids added to a baseline therapy of paracetamol and an NSAID likely result in little to no difference in cumulative opioid consumption and pain at rest at 24 h postoperatively. In addition, the evidence is very uncertain about the effect on serious adverse events. For most outcomes we did not have sufficient information to draw firm conclusions and the certainty of the evidence varied from moderate to very low. Multimodal approaches for post-operative analgesia are favoured, including paracetamol and nonsteroidal anti-inflammatory drugs. In this meta-analysis, pooled results from clinical trials are assessed to describe possible benefit of addition of glucocorticoid treatment for analgesia. The findings did not identify additional benefit, though the certainty of the evidence was not high.

This is the first of three parts of the clinical practice guideline from the European Society of Intensive Care Medicine (ESICM) on resuscitation fluids in adult critically ill patients. This part addresses fluid choice and the other two will separately address fluid amount and fluid removal. This guideline was formulated by an international panel of clinical experts and methodologists. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was applied to evaluate the certainty of evidence and to move from evidence to decision. For volume expansion, the guideline provides conditional recommendations for using crystalloids rather than albumin in critically ill patients in general (moderate certainty of evidence), in patients with sepsis (moderate certainty of evidence), in patients with acute respiratory failure (very low certainty of evidence) and in patients in the perioperative period and patients at risk for bleeding (very low certainty of evidence). There is a conditional recommendation for using isotonic saline rather than albumin in patients with traumatic brain injury (very low certainty of evidence). There is a conditional recommendation for using albumin rather than crystalloids in patients with cirrhosis (very low certainty of evidence). The guideline provides conditional recommendations for using balanced crystalloids rather than isotonic saline in critically ill patients in general (low certainty of evidence), in patients with sepsis (low certainty of evidence) and in patients with kidney injury (very low certainty of evidence). There is a conditional recommendation for using isotonic saline rather than balanced crystalloids in patients with traumatic brain injury (very low certainty of evidence). There is a conditional recommendation for using isotonic crystalloids rather than small-volume hypertonic crystalloidsin critically ill patients in general (very low certainty of evidence). This guideline provides eleven recommendations to inform clinicians on resuscitation fluid choice in critically ill patients.

Computer-aided detection versus advanced imaging for detection of colorectal neoplasia: a systematic review and network meta-analysis

Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism. To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D). We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included. Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence). Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD.

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events.This is an update of a Cochrane review first published in 2014. To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD. In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion. Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence)andepoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects onpreventing blood transfusion compared to placebo.The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain forepoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence),methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence),a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) anda biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) comparedto placebo. There was probably no difference between darbepoetin alfa andplacebo on the odds of death (any cause)(OR 0.99, 95% CI 0.81 to 1.21; moderatecertainty evidence). The comparative effects of ESAs compared with another ESAon death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderatecertainty evidence). Compared to placebo,epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa(OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin(OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence)and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension.The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data. AUTHORS' CONCLUSIONS: The comparative effects of different ESAson blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessnesswere uncertain.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiorenal risk in type 2 diabetes. However, the effect of combining these drugs remains uncertain. This systematic review aimed to evaluate the potential effectiveness and safety of combination therapy compared with monotherapy in individuals with type 2 diabetes. We systematically searched PubMed and Embase from inception to 1 May 2025 for cohort studies comparing the effect of combination therapy with SGLT2 inhibitor or GLP-1 RA monotherapy on (cardiovascular) mortality and cardiovascular or kidney endpoints in individuals with type 2 diabetes. Studies enrolling individuals with type 1 diabetes or a maximum follow-up of less than 1 year were excluded. The primary outcome was a composite of major adverse cardiovascular events (MACE). Secondary outcomes included all-cause mortality, cardiovascular mortality, hospitalisation for heart failure, a kidney composite endpoint and serious adverse events. Risk of bias was assessed with ROBINS-I. Risk ratios (RRs) and 95% CIs were pooled in random effects meta-analyses. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). We included 18 cohort studies (1,164,774 participants). In cohort studies, combination therapy was associated with a lower risk of MACE (RR 0.56 [95% CI 0.43, 0.71]; low certainty of evidence) and the kidney composite endpoint (RR 0.48 [95% CI 0.32, 0.73]; very low certainty of evidence) relative to SGLT2 inhibitor or GLP-1 RA monotherapy. Combination therapy was also associated with a lower risk of all-cause mortality (RR 0.50 [95% CI 0.40, 0.63]; low certainty of evidence), cardiovascular mortality (RR 0.26 [95% CI 0.16, 0.43]; low certainty of evidence) and hospitalisation for heart failure (RR 0.67 [95% CI 0.64, 0.71]; moderate certainty of evidence). Although safety data could not be pooled due to lack of events, no differences were observed in the risk of severe hypoglycaemia, diabetic ketoacidosis, genitourinary infections and gastrointestinal side effects. No data were reported on the risk of serious adverse events or major adverse limb events. Observational studies suggest that combining an SGLT2 inhibitor and a GLP-1 RA in type 2 diabetes may lower the risk of MACE, all-cause and cardiovascular mortality, hospitalisation for heart failure and kidney composite endpoints compared with monotherapy with either drug. Of course, residual confounding cannot be overcome but results support the need for future randomised trials of combined vs monotherapy. PROSPERO registration no. CRD42024532383.

Background: The efficacy of intravesical chemotherapy maintenance for patients with non-muscle invasive bladder cancer (NMIBC) is inferior compared to intravesical bacillus Calmette–Guerin (BCG). How intravesical chemohyperthermia (CHT) compares with BCG is under investigation.Objective: To compare the oncological outcomes and safety profile between intravesical CHT and BCG treatment for intermediate- and high-risk NMIBC.Methods: We performed a systematic review and meta-analysis of clinical studies comparing CHT with BCG for intermediate- and high-risk NMIBC patients. A comprehensive literature search on OVID MEDLINE, EMBASE, and Cochrane Library was conducted. Risk of bias was assessed by the Cochrane RoB tool and ROBINS-I. Certainty of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.Results: A total of 2,375 articles were identified and five studies were finally included. Among them, four randomised trials comprising 327 patients (CHT group: 156 patients; BCG group: 171 patients) were included in the meta-analysis. There were no significant differences in the 24–36 months recurrence rates (CHT: 29.5%, BCG: 37.4%; RR: 0.83, 95% CI 0.61–1.13; moderate certainty of evidence) and the 24–36 months progression rates (CHT: 4.4%, BCG: 7.6%, RR = 0.62, 95% CI 0.26–1.49; low certainty of evidence). There were also no significant differences in grade 1–2 adverse events (CHT group: 59.9%, BCG group 54.5%; RR = 1.10, 95% CI 0.93–1.30; moderate certainty of evidence) and grade 3 or above adverse events (CHT group: 23.2%, BCG group 22.5%; RR = 0.99, 95% CI 0.69–1.43; low certainty of evidence).Conclusions: Intravesical CHT had equivalent oncological outcomes and similar safety profile when compared to BCG maintenance therapy for patients with intermediate- and high-risk NMIBC. CHT is a possible alternative treatment in the times of BCG shortage.

Background: The efficacy of intravesical chemotherapy maintenance for patients with non-muscle invasive bladder cancer (NMIBC) is inferior compared to intravesical bacillus Calmette–Guerin (BCG). How intravesical chemohyperthermia (CHT) compares with BCG is under investigation. Objective: To compare the oncological outcomes and safety profile between intravesical CHT and BCG treatment for intermediate- and high-risk NMIBC. Methods: We performed a systematic review and meta-analysis of clinical studies comparing CHT with BCG for intermediate- and high-risk NMIBC patients. A comprehensive literature search on OVID MEDLINE, EMBASE, and Cochrane Library was conducted. Risk of bias was assessed by the Cochrane RoB tool and ROBINS-I. Certainty of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Results: A total of 2,375 articles were identified and five studies were finally included. Among them, four randomised trials comprising 327 patients (CHT group: 156 patients; BCG group: 171 patients) were included in the meta-analysis. There were no significant differences in the 24-36 months recurrence rates (CHT: 29.5%, BCG: 37.4%; RR: 0.83, 95% CI 0.61-1.13; moderate certainty of evidence) and the 24-36 months progression rates (CHT: 4.4%, BCG: 7.6%, RR=0.62, 95% CI 0.26-1.49; low certainty of evidence). There were also no significant differences in grade 1-2 adverse events (CHT group: 59.9%, BCG group 54.5%; RR=1.10, 95% CI 0.93-1.30; moderate certainty of evidence) and grade 3 or above adverse events (CHT group: 23.2%, BCG group 22.5%; RR=0.99, 95% CI 0.69-1.43; low certainty of evidence). Conclusions: Intravesical CHT had equivalent oncological outcomes and similar safety profile when compared to BCG maintenance therapy for patients with intermediate- and high-risk NMIBC. CHT is a possible alternative treatment in the times of BCG shortage.

Rapid detection of Shiga toxin-producing Escherichia coli (STEC) enables appropriate monitoring and treatment. We synthesized available evidence to compare the performance of enzyme immunoassay (EIA) and PCR tests for the detection of STEC. We searched published and gray literature for studies of STEC EIA and/or PCR diagnostic test accuracy relative to reference standards including at least one nucleic acid amplification test. Two reviewers independently screened studies, extracted data, and assessed quality with the second version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Bivariate random effects models were used to meta-analyze the clinical sensitivity and specificity of commercial EIA and PCR STEC diagnostic tests, and summary receiver operator characteristic curves were constructed. We evaluated the certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We identified 43 articles reflecting 25 260 specimens. Meta-analysis of EIA and PCR accuracy included 25 and 22 articles, respectively. STEC EIA pooled sensitivity and specificity were 0.681 (95% CI, 0.571-0.773; very low certainty of evidence) and 1.00 (95% CI, 0.998-1.00; moderate certainty of evidence), respectively. STEC PCR pooled sensitivity and specificity were 1.00 (95% CI, 0.904-1.00; low certainty of evidence) and 0.999 (95% CI, 0.997-0.999; low certainty of evidence), respectively. Certainty of evidence was downgraded because of high risk of bias. PCR tests to identify the presence of STEC are more sensitive than EIA tests, with no meaningful loss of specificity. However, given the low certainty of evidence, our results may overestimate the difference in performance.

Stem cell transplantation for systemic sclerosis.

Blood phosphorylated tau for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.

ObjectivesTo assess to what extent the overall quality of evidence indicates changes to observe intervention effect estimates when new data become available. MethodsWe conducted a meta-epidemiological study. We obtained evidence from meta-analyses of randomized trials of Cochrane reviews addressing the same health-care question that was updated with inclusion of additional data between January 2016 and May 2021. We extracted the reported effect estimates with 95% confidence intervals (CIs) from meta-analyses and corresponding GRADE (Grading of Recommendations Assessment, Development, and Evaluation) assessments of any intervention comparison for the primary outcome in the first and the last updated review version. We considered the reported overall quality (certainty) of evidence (CoE) and specific evidence limitations (no, serious or very serious for risk of bias, imprecision, inconsistency, and/or indirectness). We assessed the change in pooled effect estimates between the original and updated evidence using the ratio of odds ratio (ROR), absolute ratio of odds ratio (aROR), ratio of standard errors (RoSE), direction of effects, and level of statistical significance. ResultsHigh CoE without limitations characterized 19.3% (n = 29) out of 150 included original Cochrane reviews. The update with additional data did not systematically change the effect estimates (mean ROR 1.00; 95% CI 0.99–1.02), which deviated 1.06-fold from the older estimates (median aROR; interquartile range [IQR]: 1.01–1.15), gained precision (median RoSE 0.87; IQR 0.76–1.00), and maintained the same direction with the same level of statistical significance in 93% (27 of 29) of cases. Lower CoE with limitations characterized 121 original reviews and graded as moderate CoE in 30.0% (45 of 150), low CoE in 32.0% (48 of 150), and very low CoE in 18.7% (28 of 150) reviews. Their update had larger absolute deviations (median aROR 1.12 to 1.33) and larger gains in precision (median RoSE 0.78–0.86) without clear and consistent differences between these categories of CoE. Changes in effect direction or statistical significance were also more common in the lower quality evidence, again with a similar extent across categories (without change in 75.6%, 64.6%, and 75.0% for moderate, low, very low CoE). As limitations increased, effect estimates deviated more (aROR 1.05 with zero, 1.11 with one, 1.25 with two, 1.24 with three limitations) and changes in direction or significance became more frequent (93.2% stable with no limitations, 74.5% with one, 68.2% with two, and 61.5% with three limitations). ConclusionHigh-quality evidence without methodological deficiencies is trustworthy and stable, providing reliable intervention effect estimates when updated with new data. Evidence of moderate and lower quality may be equally prone to being unstable and cannot indicate if available effect estimates are true, exaggerated, or underestimated.

ObjectivesTo assess the beneficial and harmful effects of duloxetine versus ‘active placebo’, placebo or no intervention for adults with major depressive disorder.DesignSystematic review with meta-analysis and trial sequential analysis of...

Kidney transplantation is the preferred therapy for many patients with kidney failure. Delayed graft function (DGF) is more common in donors after cardiac death (DCD), especially those with older age, longer cold ischemia time, or higher creatinine levels. Currently, there is no agreement on the optimal immunosuppressive approach for patients at increased risk of DGF. Strategies include delaying the introduction of calcineurin inhibitors (CNI) or using an initial low dose of CNI. To evaluate the benefits and harms of delayed initiation of CNI or reduced CNI dose as initial immunosuppression therapy for kidney transplant recipients at high risk of DGF. The Cochrane Kidney and Transplant Register of Studies was searched up to 11 December 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. All randomised controlled trials (RCTs) and quasi-RCTs evaluating delayed versus early initiation of CNI or reduced versus standard initial dose of CNI in kidney transplant recipients at high risk of DGF. Three authors independently assessed study eligibility, and two assessed the risk of bias, certainty of evidence, extracted the data, and performed the analysis. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and as mean difference (MD) with 95% CI for continuous outcomes. Statistical analysis was performed using the random-effects model. Risk of bias was assessed with the Cochrane risk of bias assessment tool 1.0, and the certainty of the evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods, which are presented in the summary of findings tables. We included 12 studies (2230 randomised participants). All studies were performed in Europe. Around 60% of the participants were males, reflecting the expected proportion in the population on kidney replacement therapy in Europe. Most studies had insufficient information to judge adequate random sequence generation and, or allocation concealment. All studies were unblinded, and judged as high risk of bias for DGF if the definition was based on need for dialysis, and for acute rejection if the diagnosis did not require a biopsy. Overall, the level of certainty was low, and reasons to downgrade were mainly due to risk of bias and imprecision. Delayed versus early initiation of CNI There may be little or no difference in DGF between the groups (6 studies, 905 recipients: RR 0.92, 95% CI 0.76 to 1.12; low certainty evidence) or in acute rejection (8 studies, 1295 recipients: RR 1.02, 95% CI 0.75 to 1.40; low certainty evidence). Delaying the initiation of CNI probably makes little or no difference to eGFR (6 studies, 851 recipients: MD -0.81 mL/min, 95% CI -3.33 to 1.72; moderate certainty evidence). Delaying the initiation of CNI may make little or no difference to graft loss censored for death (8 studies, 1295 recipients: RR 1.58, 95% CI 0.68 to 3.65; very low certainty evidence) or to all-cause death (8 studies, 907 recipients: RR 1.08, 95% CI 0.54 to 2.14; very low certainty evidence) although the evidence is very uncertain. There is probably little or no difference in all infections between the groups (6 studies, 1226 recipients: RR 1.10, 95% CI 0.97 to 1.25; moderate certainty evidence). Low versus standard initial dose of CNI There may be little or no difference to DGF between the groups (5 studies, 983 recipients: RR 1.16, 95% CI 0.90 to 1.50; low certainty evidence) or in acute rejection (5 studies, 947 recipients: RR 0.83, 95% CI 0.52 to 1.30; low certainty evidence). Starting CNI at a lower dose may make little or no difference to eGFR (5 studies, 935 recipients: MD 4.06 mL/min, 95% CI -1.36 to 9.48, low certainty evidence). Starting CNI at a lower dose may make little or no difference to graft loss censored for death, although the evidence is very uncertain (5 studies, 983 recipients: RR 1.05, 95% CI 0.64 to 1.71; very low certainty evidence), or to all-cause death (4 studies, 521 recipients: RR 1.01, 95% CI 0.41 to 2.47; low certainty evidence). There is probably little or no difference in all infections between the groups (4 studies, 828 recipients: RR 0.87, 95% CI 0.71 to 1.07; moderate certainty evidence). There may be little or no difference in DGF or acute rejection when delaying the start of CNI or when starting it at a lower dose in kidney transplant recipients at high risk of DGF. The available data are of low certainty.