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Take Home Message This systematic review and meta-analysis, based on updated individual participant data, demonstrates that cisplatin-based adjuvant chemotherapy is a valid option for improving outcomes for muscle-invasive bladder cancer., Context Our prior systematic review and meta-analysis of individual participant data (IPD) suggesting a benefit of adjuvant chemotherapy for muscle-invasive bladder cancer was limited by the number and size of included randomised trials. We have updated results to include additional trials, providing the most up-to-date and reliable evidence of the effects of this treatment. Objective To investigate the role of adjuvant cisplatin-based chemotherapy in the treatment of muscle-invasive bladder cancer. Evidence acquisition Published and unpublished trials were sought via searches of bibliographic databases, trials registers, conference proceedings, and hand searching. Updated IPD were centrally collected, checked, and analysed. Results from individual randomised controlled trials (RCTs) were combined using a two-stage fixed-effect model. Prespecified analyses explored any variation in effect by trial and participant characteristics. Evidence synthesis Analyses of ten RCTs (1183 participants) demonstrated a benefit of cisplatin-based adjuvant chemotherapy on overall survival (hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70–0.96, p = 0.02). This represents an absolute improvement in survival of 6% at 5 yr, from 50% to 56%, and a 9% absolute benefit when adjusted for age, sex, pT stage, and pN category (HR = 0.77, 95% CI = 0.65–0.92, p = 0.004). There was no clear evidence that the effect varied by trial or participant characteristics. Adjuvant chemotherapy was also shown to improve recurrence-free survival (HR = 0.71, 95% CI = 0.60–0.83, p

Objective Methods for meta-analysis of studies with individual participant data and continuous exposure variables are well described in the statistical literature but are not widely used in clinical and epidemiological research. The purpose of this case study is to make the methods more accessible. Study Design and Setting A two-stage process is demonstrated. Response curves are estimated separately for each study using fractional polynomials. The study-specific curves are then averaged pointwise over all studies at each value of the exposure. The averaging can be implemented using fixed effects or random effects methods. Results The methodology is illustrated using samples of real data with continuous outcome and exposure data and several covariates. The sample data set, segments of Stata and R code, and outputs are provided to enable replication of the results. Conclusion These methods and tools can be adapted to other situations, including for time-to-event or categorical outcomes, different ways of modelling exposure-outcome curves, and different strategies for covariate adjustment.

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© 2020 Elsevier LtdThe patho-etiology of mental disorders with onset in childhood or adolescence remains largely unknown. We conducted an umbrella review of meta-analyses (MAs) on environmental factors associated with mental disorders with onset in childhood/adolescence. We searched Pubmed-MEDLINE/EMBASE/PsycInfo databases, last search April 29th, 2020. Quality of MAs was measured with AMSTAR-2. Out of 6851 initial references, ten articles met inclusion criteria, providing 23 associations between 12 potential environmental factors and nine disorders (cases: 8884; N = 3,660,670). While almost half of the associations were nominally significant, none of them met criteria from either convincing or highly suggestive evidence. A single association was supported by suggestive evidence (maternal exposure to lithium or antipsychotics with neuromotor deficits), but it was affected by confounding by indication. Ten more associations had weak evidence, and 12 associations were not statistically significant. Quality of meta-analyses was rated as high in two, moderate in one, low in four, critically low in two, and not pertinent in one (individual participant data). Methodologically-sound research is needed in this field.

Summary Background Exposure to faecal contamination is believed to be associated with child diarrhoea and possibly stunting; however, few studies have explicitly measured the association between faecal contamination and health. We aimed to assess individual participant data (IPD) across multiple trials and observational studies to quantify the relationship for common faecal–oral transmission pathways. Methods We did a systematic review and meta-analysis of IPD from studies identified in an electronic search of PubMed, Web of Science, and Embase on May 21, 2018. The search was done in English, but full texts published in French, Portuguese, and Spanish were also reviewed. Eligible studies quantified (1) household-level faecal indicator bacteria concentrations along common faecal-oral transmission pathways of drinking water, soil, or food, on children's hands or fomites, or fly densities in food preparation areas; and (2) individual-level diarrhoea or linear growth measures for children younger than 5 years in low-income and middle-income countries. For the diarrhoea analysis, all definitions of diarrhoea were eligible but studies were excluded if they used a recall period longer than 7 days. For the linear growth analysis (using height-for-age Z scores [HAZ]), cross-sectional studies were excluded, because of the absence of longitudinal environmental contamination data measured before the growth outcomes. We used multilevel generalised mixed-effects models to estimate the odds ratio (OR) for diarrhoea and the difference in HAZ scores for individual studies associated with a 1-log10 higher measure of faecal contamination. Estimates from each study were combined under a random-effects meta-analysis framework. The study protocol was pre-registered with PROSPERO (CRD42018102114). Findings From 72 eligible studies, we included IPD for 20 studies in the meta-analyses, totalling 54 225 diarrhoea or linear growth observations matched to faecal indicator bacteria concentrations in drinking water, and a further 35 010 observations with faecal contamination data for the other transmission pathways. Child diarrhoea was associated with 1-log10 higher faecal indicator bacteria concentrations in drinking water (OR 1·09, 95% CI 1·04 to 1·13; p=0·0002, I2=34%, 95% CI 0 to 62) and on children's hands (1·11, 1·02 to 1·22; p=0·021, I2=0%, 0 to 71). Lower HAZ scores were associated with 1-log10 higher median faecal indicator bacteria concentrations in drinking water (HAZ −0·04, 95% CI −0·06 to −0·01; p=0·0054; I2=19%, 95% CI 0 to 63) and on fomites (–0·06, −0·12 to 0·00; p=0·044, I2=57%, 0 to 90). Interpretation Although summary measures from individual studies often report little or no effect of measured faecal contamination on child health, this multi-study IPD analysis indicates that household faecal indicator bacteria concentrations are associated with important adverse health outcomes in young children. Improved direct measures of exposure and enteric pathogens could help to better characterise the relationship and inform intervention design in future studies. Funding None.

Meta-analysis is usually performed using aggregate data. Aggregate data refer to the summary of individual participant data (IPD) on the investigated outcomes and related characteristics obtained from the trial reports. In the case of binary outcome data, the aggregate data include the number of participants who experienced the event (eg, bond failures per treatment group) from the total randomized in the trial. For continuous outcomes, such as overjet, intercanine, and intermolar width or space closure in millimeters, the researcher extracts the number of participants, the mean and standard deviation of the outcome measured in each trial arm. In terms of characteristics, aggregate data can include the summary of participant- and clinical-related characteristics, such as the mean age, gender distribution across arms, and the mean follow-up period. Although aggregate data allow for a straightforward analysis, they cannot always uncover the true associations between treatment effects and characteristics. Over time, the well-documented limitations of aggregate data analysis have initiated a paradigm shift for collecting and re-analyzing IPD, whenever possible, after the principles and procedures of conventional systematic reviews.1,2 Systematic reviews of IPD have gained popularity in the therapeutic, diagnostic, and prognostic research in numerous health care fields.3

Objective : We describe a systematic approach to preparing data in the conduct of Individual Participant Data (IPD) analysis. Study design and setting : A guidance paper proposing methods for preparing individual participant data for meta-analysis from multiple study sources, developed by consultation of relevant guidance and experts in IPD. We present an example of how these steps were applied in checking data for our own IPD meta analysis (IPD-MA). Results : We propose five steps of Processing, Replication, Imputation, Merging, and Evaluation to prepare individual participant data for meta-analysis (PRIME-IPD). Using our own IPD-MA as an exemplar, we found that this approach identified missing variables and potential inconsistencies in the data, facilitated the standardization of indicators across studies, confirmed that the correct data were received from investigators, and resulted in a single, verified dataset for IPD-MA. Conclusion : The PRIME-IPD approach can assist researchers to systematically prepare, manage and conduct important quality checks on IPD from multiple studies for meta-analyses. Further testing of this framework in IPD-MA would be useful to refine these steps.

Summary Background The efficacy of antipsychotics across the initial severity range in patients with acute mania remains unclear. Therefore, we examined the influence of baseline severity on the efficacy of olanzapine. Methods We did an individual participant data meta-analysis of double-blind, randomised controlled trials that compared olanzapine with placebo, identified through searches of the ClinicalStudyDataRequest.com database on Feb 2, 2016. We included patients with acute mania associated with bipolar I disorder. We examined the association between baseline and change scores on the Young Mania Rating Scale (YMRS; range 0–60) up to 3 weeks for olanzapine versus placebo groups using eight increasingly complex competing mixed-effects models for repeated measures. Findings We identified 33 reports, five (15%) of which were eligible and contained data for 939 patients (552 received olanzapine; 387 received placebo). The interaction between baseline severity and treatment was significant (β=0·22, 95% CI 0·05–0·39; p=0·013). The greater the baseline severity, the greater the magnitude of the differences between olanzapine and placebo was expected. The mean estimated YMRS scores were reduced at 3 weeks in both groups, but were greater with olazapine than placebo by 2·56 points for patients with a baseline score of 20–25 (9·26 for olanzapine vs 6·70 for placebo; effect size 0·35, 95% CI 0·11–0·60), by 4·74 points for a baseline score of 25–35 (14·25 vs 9·51; 0·58, 0·34–0·86), and by 8·01 points for a baseline score of 35–60 (21·72 vs 13·71; 0·70, 0·31–1·23). Interpretation Benefits of olanzapine can be expected for patients across the full spectrum of symptom severity who are likely to be treated for acute mania. Less severely ill patients seem to benefit less in terms of olanzapine efficacy, but still experience the same side-effects as more severely ill patients. Thus, clinicians and patients should carefully consider the benefit-to-risk ratio of olanzapine and its additional, prophylactic effect against relapse in the long term. The generalisability of these results to other antipsychotics, trial designs, and medical conditions remains to be established. Funding None.

Meta-analyses of individual participant data (MIPDs) offer many advantages and are considered the highest level of evidence. However, MIPDs can be seriously compromised when they are not solidly founded upon a systematic review. These data-intensive collaborative projects may be led by experts who already have deep knowledge of the literature in the field and of the results of published studies and how these results vary based on different analytical approaches. If investigators tailor the searches, eligibility criteria, and analysis plan of the MIPD, they run the risk of reaching foregone conclusions. We exemplify this potential bias in a MIPD on the association of body mass index with mortality conducted by a collaboration of outstanding and extremely knowledgeable investigators. Contrary to a previous meta-analysis of group data that used a systematic review approach, the MIPD did not seem to use a formal search: it considered 239 studies, of which the senior author was previously aware of at least 238, and it violated its own listed eligibility criteria to include those studies and exclude other studies. It also preferred an analysis plan that was also known to give a specific direction of effects in already published results of most of the included evidence. MIPDs where results of constituent studies are already largely known need safeguards to their validity. These may include careful systematic searches, adherence to the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines, and exploration of the robustness of results with different analyses. They should also avoid selective emphasis on foregone conclusions based on previously known results with specific analytical choices.

Background: Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure (SBP) levels achieved with intravenous nicardipine immediately after onset of intracerebral haemorrhage (ICH) on clinical outcomes were determined. Methods: A systematic review and individual patient data analysis of articles before October 1, 2020 identified on PubMed were performed. Prospective studies involving hyperacute ICH adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale (mRS) were eligible. Outcomes included death or disability at 90 days, defined as an mRS score of 4-6, and haematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. Findings: Three studies met the eligibility criteria. Of 1,271 patients overall, 1,265 (age 62.6±13.0 years, 484 women) with available SBP data were included. Death or disability occurred in 38.2%, and haematoma expansion occurred in 17.4%. Mean hourly SBP during the initial 24 h was positively associated with death or disability [adjusted odds ratio (aOR) 1.12, 95% CI 1.00–1.26 per 10 mmHg] and haematoma expansion (1.16, 1.02–1.32). The association of SBP with death or disability was modified by race, baseline diastolic BP, and study population (higher SBP increased the risk in Asians, aOR 1.26, 95% CI 1.10–1.43). Mean hourly SBP from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Slower lowering of SBP to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00–1.05, per hour). Interpretation: Rapid lowering of SBP by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute ICH decreased early haematoma expansion and 90-day death or disability without increasing serious adverse events. Funding: Japan Agency for Medical Research and Development. Conflict of Interest: All of the following conflicts are outside the submitted work.Toyoda reports personal fees from Daiichi-Sankyo, Bayer Yakuhin, Bristol-Myers-Squibb (BMS), and Nippon Boehringer-Ingelheim (NBI). Ihara reports grants from Panasonic, Shimadzu Corporation, BMS, Otsuka Pharmaceutical, and personal fees from Daiichi-Sankyo, Eisai, and Bayer Yakuhin.Itabashi reports grants from Tohoku Fukushi University and NBI. Yamagami reports research grants from BMS; lecturer’s fees from Stryker, Terumo, Medtronic, Medico’s Hirata, Johnson and Johnson, Bayer, Daiichi-Sankyo, BMS, NBI, Takeda, and Otsuka Pharmaceutical; and membership of the advisory boards for Daiichi-Sankyo. Itabashi reports honoraria from Bayer, Eisai, BMS, Daiichi Sankyo, NBI, Takeda, Otsuka Pharmaceutical, Tanabe-Mitsubishi Parma, Pfizer, GE Healthcare Japan, Stryker, Medtronic, and Johnson and Johnson, and research support from Tohoku Fukushi University and NBI. Sakai reports grants from Daiichi-Sankyo, Jimro, Medtronic, Terumo, and honoraria from Asahi-Intec, Biomedical Solutions, Daiichi-Sankyo, Medtronic, and Stryker. Inoue reports personal fees from Daiichi-Sankyo, Bayer, BMS, and Medtronic. Minematsu reports personal fees and other from Bayer Yakuhin and AstraZeneca, personal fees from Otsuka Pharmaceutical, NBI, Mitsubishi Tanabe Pharma, BMS, Pfizer, Japan Stryker, Daiichi-Sankyo, Astellas Pharma, Nippon Chemiphar, and Fuji Film RI Pharma; and other (Advisory Board) from CSL Behring, Medico’s Hirata, EPS Corporation, HEALIOS K.K., and T-PEC Corporation. Koga reports honoraria from Bayer Yakuhin, Otsuka, Daiichi-Sankyo, and NBI, scientific advisory board from Ono, and research support from Takeda, Daiichi-Sankyo, NBI, and Shionogi.None of the other authors has any conflicts of interest to declare. Ethical Approval: The study design followed PRISMA guidelines for IPD systematic reviews. Ethical approval to perform the present IPD analysis was obtained from the site of the corresponding author. The study is registered with PROSPERO (CRD42020213857).

Background: Randomized trials have shown that trans-nasal evaporative cooling initiated during CPR (i.e. intra-arrest) effectively lower core body temperature in out-of-hospital cardiac arrest patients. However, these trials may have been underpowered to detect significant differences in neurologic outcome, especially in patients with initial shockable rhythm. Methods: We conducted a pooled analysis of individual data from two randomised trials including 843 patients who eventually received the allocated intervention and with available outcome. Primary outcome was survival with favourable neurological outcome at hospital discharge (Cerebral Performance Category [CPC] of 1-2) according to the initial rhythm (shockable vs. non-shockable). Secondary outcomes included complete neurological recovery (CPC 1) at hospital discharge. Findings: Among the 325 patients with initial shockable rhythms, favourable neurological outcome was observed in 54/158 (34.2%) patients in the intervention and 40/167 (24.0%) in the control group (RR 1.43 [confidence intervals, CIs 1.01-2.02]). Complete neurological recovery was observed in 40/158 (25.3%) in the intervention and 27/167 (16.2%) in the control group (RR 1.57 [CIs 1.01-2.42]. Among the 518 patients with initial non-shockable rhythms, favourable neurological outcome was observed in 10/250 (4.0%) patients in the intervention and 13/267 (4.9%) in the control group (RR 0.82 [CIs 0.37-1.84]; complete neurological recovery was observed in 4/250 (1.6%) and 5/267 (1.9%) patients, respectively (RR 0.85 [CIs 0.23-3.15]. Interpretation: In this pooled analysis of individual data, intra-arrest cooling was associated with a significant increase in favourable neurological outcome in out-of-hospital cardiac arrest patients with initial shockable rhythms. No effects were observed in patients with initial non-shockable rhythms. Funding Statement: No funding has been received for this study. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Ethics and institutional committees in each participating country approved the study protocols and written consent was obtained from closest relative or a legal representative of each patient after hospital admission and, at a later stage, from each patient who showed neurological recovery. Both studies were conducted according to the requirements of the Declaration of Helsinki.

Purpose Although the outcomes of bariatric surgery (BS) in patients with ventricular assist devices (VADs) are promising, the evidence is limited to case reports or very small retrospective cohorts. Hence, no study has tried or been able to identify potential predictors of successful outcomes in this high-risk population, which could aid patient selection. Methods This study combined the individual participant data (IPD) of patients with VADs who underwent BS at Ochsner Medical Center (OMC) and patients of references identified through a systematic search in ClinicalTrials.gov, Cochrane, Embase, and PubMed. Patients who underwent BS during VAD support, as staged interventions, were included if their IPD for post-BS BMI were available. Datasets from the literature search and OMC were merged in an IPD meta-analysis to identify predictors of the composite outcome: body mass index (BMI) Results Among the 38 patients, 18 (58%) were male, the mean age was 42 (±12.5) years, and 33 (86.9%) underwent sleeve gastrectomy, while 5 (13.2%) had Roux-en-Y gastric bypass. During a follow-up of 20 (12-30) months, 30 patients achieved the composite outcome, among whom 22 were listed for HT, 17 underwent HT, and 3 experienced recovery and VAD explantation. Time to composite outcome was 10 (3-17) months. Among all baseline variables, preoperative BMI was the only statistically significant predictor for achieving the composite outcome (p Conclusion Preoperative BMI was the only statistically significant predictor for the composite clinical outcome due to its impact in postoperative BMI during follow-up. Most patients received HT. This reflects the important role of a BMI ≥35 kg/m2 as a contraindication for HT. It is likely that more patients, especially those with shorter follow-up, would have reached the composite outcome after primary references were published or conclusion of this study. Future larger studies may be able to identify additional predictors of clinical outcomes.

Background: Digital breast tomosynthesis (DBT) improves breast cancer (BC) detection compared to mammography, however, it is unknown whether this reduces interval cancer rate (ICR) at follow-up. Methods: Using individual participant data (IPD) from DBT screening studies (identified via periodic literature searches July 2016 to November 2019) we performed an IPD meta-analysis. We estimated ICR for DBT-screened participants and the difference in pooled ICR for DBT and mammography-only screening, and compared interval BC characteristics. Two-stage meta-analysis (study-specific estimation, pooled synthesis) of ICR included random-effects, adjusting for study and age, and was estimated in age and density subgroups. Comparative screening sensitivity was calculated using screen-detected and interval BC data. Findings: Four prospective DBT studies, from European population-based programs, contributed IPD for 66,451 DBT-screened participants: age-adjusted pooled ICR was 13.17/10,000 (95%CI: 8.25-21.02). Pooled ICR was higher in the high-density (21.08/10,000; 95%CI: 6.71-66.27) than the low-density (8.63/10,000; 95%CI: 5.25-14.192) groups (P = 0.03) however estimates did not differ across age-groups (P = 0.32). Based on two studies that also provided data for 153,800 mammography screens (age-adjusted ICR 17.69/10,000; 95%CI: 13.22-23.66), DBT's pooled ICR was 16.83/10,000 (95%CI: 11.89-23.82). Comparative meta-analysis showed a non-significant difference in ICR (-0.44/10,000; 95%CI: -11.00-10.11) and non-significant difference in screening sensitivity (6.79%; 95%CI: -0.73-14.87%) between DBT and DM but a significant pooled difference in cancer detection rate of 33.49/10,000 (95%CI: 23.88-43.10). Distribution of interval BC prognostic characteristics did not differ between screening modalities except that those occurring in DBT-screened participants were significantly more likely to be negative for axillary-node metastases (P = 0.005). Interpretation: Although heterogeneity in ICR estimates and few datasets limit recommendations, there was no difference between DBT and mammography in pooled ICR despite DBT increasing cancer detection. (C) 2021 The Author(s). Published by Elsevier Ltd.

Summary Background Although overt manifestations of cardiovascular disease (CVD) rarely emerge before adulthood, CVD risk factors are often present in adolescents. However, the prevalence and magnitude of behavioural CVD risk factors in adolescents in low-income and middle-income countries remains unclear. We estimated the magnitude and co-occurrence of behavioural CVD risk factors in adolescents aged 12–15 years for 65 low-income and middle-income countries between 2003 and 2011. Methods We extracted Global School-Based Student Health Surveys (GSHS) datasets from the Centers for Disease Control and Prevention (CDC) website. Pooled prevalence estimates of current tobacco use, alcohol use, low fruit and vegetable intake, low physical activity, obesity and co-occurrence of CVD risk factors for WHO regions and overall, was calculated with random-effects meta-analysis. We explored potential sources of heterogeneity for each CVD risk factor through random-effects meta-regression analysis. Findings Between 2003 and 2011, of 169 369 adolescents, 12·1% (95% CI 10·2–14·1) used tobacco, 15·7% (12·3–19·5) used alcohol, 74·3% (71·9 −76·5) had low fruit and vegetable intake, 71·4% (69·5–73·3) reported low physical activity and 7·1% (5·6–8·7) were obese. The pooled regional prevalence of exposure to three or more CVD risk factors was lowest in the southeast Asian region (3·8%, 95% CI 1·2–7·5) and highest in the western Pacific region (18·6%, 12·8–25·3). Substantial heterogeneities within and across regions were not fully explained by major study characteristics. Interpretation In low-income and middle-income countries, adolescents carry a substantial burden of behavioural CVD risk factors, which tend to co-occur. Surveillance, prevention, detection, and control initiatives are a global health priority. Funding None.

Placenta-mediated pregnancy complications, including pre-eclampsia, placental abruption, birth of a small-for-gestational age infant and late pregnancy loss, are common and cause significant morbidity and mortality. The use of antepartum low-molecular-weight heparin (LMWH) prophylaxis to prevent recurrent placenta-mediated pregnancy complications became common practice despite limited and conflicting evidence supporting its use. Unfortunately, differences in the study design of individual randomized controlled trials have limited comparison across trials. In this talk we will review data from an individual patient data meta-analysis that challenges the role of LMWH in preventing recurrent placenta-mediated pregnancy complications.

To assess whether inhaled nitric oxide (iNO) improves survival without bronchopulmonary dysplasia (BPD) for preterm African American infants.An individual participant data meta-analysis was conducted, including 3 randomized, placebo-controlled trials that enrolled infants born at 34 weeks of gestation receiving respiratory support, had at least 15% (or a minimum of 10 infants in each trial arm) of African American race, and used a starting iNO of5 parts per million with the intention to treat for 7 days minimum. The primary outcome was a composite of death or BPD. Secondary outcomes included death before discharge, postnatal steroid use, gross pulmonary air leak, pulmonary hemorrhage, measures of respiratory support, and duration of hospital stay.Compared with other races, African American infants had a significant reduction in the composite outcome of death or BPD with iNO treatment: 49% treated vs 63% controls (relative risk, 0.77; 95% CI, 0.65-0.91; P = .003; interaction P = .016). There were no differences between racial groups for death. There was also a significant difference between races (interaction P = .023) of iNO treatment for BPD in survivors, with the greatest effect in African American infants (P = .005). There was no difference between racial groups in the use of postnatal steroids, pulmonary air leak, pulmonary hemorrhage, or other measures of respiratory support.iNO therapy should be considered for preterm African American infants at high risk for BPD. iNO to prevent BPD in African Americans may represent an example of a racially customized therapy for infants.

Currently the characteristics and potential mechanism of idiopathic ventricular fibrillation (IVF) are still not well known. Though implantable cardioverter defibrillator (ICD) is recommended as one first-line treatment for IVF, the prognosis and recurrent rate seem to be unsatisfactory. This

Background This programme of overviews of randomised trials was established to investigate the effects of angiotensin-converting-enzyme (ACE) inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients. We did separate overviews of trials comparing active treatment regimens with placebo, trials comparing more intensive and less intensive blood-pressure-lowering strategies, and trials comparing treatment regimens based on different drug classes. Methods The hypotheses to be investigated, the trials to be included, and the outcomes to be studied were all selected before the results of any participating trial were known. Individual participant data or group tabular data were provided by each trial and combined by standard statistical techniques. Findings The overview of placebo-controlled trials of ACE inhibitors (four trials, 12,124 patients mostly with coronary heart disease) revealed reductions in stroke (30% [95% CI 15-43]), coronary heart disease (20% [11-28]), and major cardiovascular events (21% [14-27]). The overview of placebo-controlled trials of calcium antagonists (two trials, 5520 patients mostly with hypertension) showed reductions in stroke (39% [15-56]) and major cardiovascular events (28% [13-41]). In the overview of trials comparing blood-pressure-lowering strategies of different intensity (three trials, 20,408 patients with hypertension), there were reduced risks of stroke (20% [2-35]), coronary heart disease (19% [2-33]), and major cardiovascular events (15% [4-24]) with more intensive therapy. In the overviews comparing different antihypertensive regimens (eight trials, 37,872 patients with hypertension), several differences in cause-specific effects were seen between calcium-antagonist-based therapy and other regimens, but each was of borderline significance. Interpretation Strong evidence of benefits of ACE inhibitors and calcium antagonists is provided by the overviews of placebo-controlled trials. There is weaker evidence of differences between treatment regimens of differing intensities and of differences between treatment regimens based on different drug classes. Data from continuing trials of blood-pressure-lowering drugs will substantially increase the evidence available about any real differences that might exist between regimens.

Comment on Effectiveness of electronic fetal monitoring with additional ST analysis in vertex singleton pregnancies at >36 weeks of gestation: an individual participant data metaanalysis