One-stage Individual Participant Data Research Articles

Blood pressure-lowering and risk of cancer: an individual participant-level data meta-analysis and mendelian randomisation studies

Abstract Background The current body of randomised evidence concerning the effect of blood pressure lowering on the risk of cancer remains limited. Purpose We leveraged the strengths of both randomised controlled trials (RCTs) and genomic information to examine this question. Methods Individual-level data from 314,016 participants from 42 RCTs were pooled to investigate the effect of blood pressure lowering on the risk of cancer through one-stage individual participant data (IPD) meta-analysis. The primary outcome was incident cancer, defined as the first occurrence of any cancer diagnosed after randomisation. Pre-specified subgroup analyses were conducted to assess heterogeneity in effect by follow-up time and baseline age groups, sex, body mass index categories, smoking status and previous use of antihypertensive drugs. Secondary outcomes were cause-specific cancer death and site-specific cancer risk comprising breast, colorectal, kidney, lung, prostate, and skin. Cox proportional hazard regression, stratified by trials, were used for statistical analyses. For site-specific cancers, analyses were complemented with Mendelian randomisation analyses using naturally randomised genetic variants associated with blood pressure lowering, retrieved from genome-wide association studies involving participants of European ancestry. Results Over a median of 4 years (interquartile range 2), 17,954 participants in RCTs were diagnosed with cancer of any type and 4,878 participants were reported to have died with cancer as the cause of death. In the IPD meta-analysis that compared the treatment arm with the comparator, no associations were identified between reductions in either systolic or diastolic blood pressure and the risk of incident cancer (hazard ratios [HRs] per 5 mmHg reduction in systolic and per 3 mmHg diastolic blood pressure were 1.03 (95% confidence interval [CI] 0.99-1.06) and 1.03 [0.98-1.07], respectively). We also found no pattern of increasing or decreasing relative risk for incident cancer during the follow-up period, nor was there evidence of heterogeneity in treatment effects across baseline subgroups. No effect on the risk of cause-specific cancer death was identified for either systolic or diastolic blood pressure lowering. Considering site-specific cancers, we also found no evidence of effect, except for a possible link with lung cancer risk, with HRs of 1.17 [99.5% CI 1.02-1.32] for systolic blood pressure and 1.17 [99.5% CI 0.98-1.36] for diastolic blood pressure lowering. In Mendelian randomisation studies, no association was observed for genetically determined systolic and diastolic blood pressure and all the considered site-specific cancers, including overall lung cancer and its subtypes. Conclusion We found no consistent randomised evidence to suggest that blood pressure-lowering has a substantial effect, whether increasing or decreasing, on incident cancer, cause-specific cancer death, or selected site-specific cancers.

Prevalence of subclinical pulmonary tuberculosis in adults in community settings: an individual participant data meta-analysis

Subclinical pulmonary tuberculosis, which presents without recognisable symptoms, is frequently detected in community screening. However, the disease category is poorly clinically defined. We explored the prevalence of subclinical pulmonary tuberculosis according to different case definitions. We did a one-stage individual participant data meta-analysis of nationally representative surveys that were conducted in countries with high incidence of tuberculosis between 2007 and 2020, that reported the prevalence of pulmonary tuberculosis based on chest x-ray and symptom screening in participants aged 15 years and older. Screening and diagnostic criteria were standardised across the surveys, and tuberculosis was defined by positive Mycobacterium tuberculosis sputum culture. We estimated proportions of subclinical tuberculosis for three case definitions: no persistent cough (ie, duration ≥2 weeks), no cough at all, and no symptoms (ie, absence of cough, fever, chest pain, night sweats, and weight loss), both unadjusted and adjusted for false-negative chest x-rays and uninterpretable culture results. We identified 34 surveys, of which 31 were eligible. Individual participant data were obtained and included for 12 surveys (620 682 participants) across eight countries in Africa and four in Asia. Data on 602 863 participants were analysed, of whom 1944 had tuberculosis. The unadjusted proportion of subclinical tuberculosis was 59·1% (n=1149/1944; 95% CI 55·8-62·3) for no persistent cough and 39·8% (773/1944; 36·6-43·0) for no cough of any duration. The adjusted proportions were 82·8% (95% CI 78·6-86·6) for no persistent cough and 62·5% (56·6-68·7) for no cough at all. In a subset of four surveys, the proportion of participants with tuberculosis but without any symptoms was 20·3% (n=111/547; 95% CI 15·5-25·1) before adjustment and 27·7% (95% CI 21·0-36·4) after adjustment. Tuberculosis without cough, irrespective of its duration, was more frequent among women (no persistent cough: adjusted odds ratio 0·79, 95% CI 0·63-0·97; no cough: adjusted odds ratio 0·76, 95% CI 0·62-0·93). Among participants with tuberculosis, 29·1% (95% CI 25·2-33·3) of those without persistent cough and 23·1% (18·8-27·4) of those without any cough had positive smear examinations. The majority of people in the community who have pulmonary tuberculosis do not report cough, a quarter report no tuberculosis-suggestive symptoms at all, and a quarter of those not reporting any cough have positive sputum smears, suggesting infectiousness. In high-incidence settings, subclinical tuberculosis could contribute considerably to the tuberculosis burden and to Mycobacterium tuberculosis transmission. Mr Willem Bakhuys Roozeboom Foundation.

Comparing body composition between the sweet-liking phenotypes: experimental data, systematic review and individual participant data meta-analysis.

Legislation aimed at reducing sugar intake assumes that sweet-liking drives overconsumption. However, evidence that a greater liking for sweet taste is associated with unhealthier body size is mixed and complicated by relatively small samples, an overreliance on body mass index (BMI) and lack of classification using sweet-liking phenotypes. We first examined body size data in two larger samples with sweet-liking phenotyping: extreme sweet-likers, moderate sweet-likers and sweet-dislikers. Adults (18-34yrs), attended a two-session lab-based experiment involving phenotyping for sweet-liking status and a bioelectrical impedance body composition measurement (Experiment One: N = 200; Experiment Two: N = 314). Secondly, we conducted an individual participant data (IPD) meta-analysis: systematic searches across four databases identified 5736 potential articles. Of these, 53 papers met our search criteria: a taste assessment that measured liking using sucrose (>13.7% w/v), which allowed sweet-liking phenotyping and included either BMI, body fat percentage (BF%), fat-free mass (FFM) or waist-circumference. A significant effect of sweet-liking phenotype on FFM was found in both Experiment One and Two, with extreme sweet-likers having significantly higher FFM than sweet-dislikers. In Experiment One, sweet-dislikers had a significantly higher BF% than extreme sweet-likers and moderate sweet-likers. However, as these data are from one research group in a young, predominantly westernised population, and the results did not perfectly replicate, we conducted the IPD meta-analyses to further clarify the findings. Robust one-stage IPD meta-analyses of 15 studies controlling for sex revealed no significant differences in BF% (n = 1836) or waist-circumference (n = 706). For BMI (n = 2368), moderate sweet-likers had slightly lower BMI than extreme sweet-likers, who had the highest overall BMI. Most interestingly, for FFM (n = 768), moderate sweet-likers and sweet-dislikers showed significantly lower FFM than extreme sweet-likers. The higher BMI often seen in sweet-likers may be due to a larger FFM and questions the simple model where sweet liking alone is a risk factor for obesity.

The association between obesity severity and food reward in adolescents with obesity: a one-stage individual participant data meta-analysis.

Food reward and cue reactivity have been linked prospectively to problematic eating behaviours and excess weight gain in adults and children. However, evidence to date in support of an association between degree of adiposity and food reward is tenuous. A non-linear relationship between reward sensitivity and obesity degree has been previously proposed, suggesting a peak is reached in mild obesity and decreases in more severe obesity in a quadratic fashion. To investigate and characterise in detail the relationship between obesity severity, body composition, and explicit and implicit food reward in adolescents with obesity. Data from seven clinical trials in adolescents with obesity were aggregated and analysed in an independent participant data meta-analysis. Linear and curvilinear relationships between the degree of obesity and explicit and implicit reward for sweet and high fat foods were tested in fasted and fed states with BMI-zscore as a continuous and discrete predictor using clinically recognised partitions. Although positive associations between obesity severity and preference for high-fat (i.e. energy dense) foods were observed when fasted, none reached significance in either analysis. Conversely, adiposity was reliably associated with lower reward for sweet, particularly when measured as implicit wanting (p = 0.012, ηp2 = 0.06), independent of metabolic state. However, this significant association was only observed in the linear model. Fat distribution was consistently associated with explicit and implicit preference for high-fat foods. A limited relationship was demonstrated between obesity severity and food reward in adolescents, although a lower preference for sweet could be a signal of severe obesity in a linear trend. Obesity is likely a heterogenous condition associated with multiple potential phenotypes, which metrics of body composition may help define. NCT02925572: https://classic. gov/ct2/show/NCT02925572 . NCT03807609: https://classic. gov/ct2/show/NCT03807609 . NCT03742622: https://classic. gov/ct2/show/NCT03742622 . NCT03967782: https://classic. gov/ct2/show/NCT03967782 . NCT03968458: https://classic. gov/ct2/show/NCT03968458 . NCT04739189: https://classic. gov/ct2/show/NCT04739189 . NCT05365685: https://www. gov/study/NCT05365685?tab=history .

Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events

The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated. To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials. PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023. For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included. Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]). One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day). A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]). Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis

Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. National Institute for Health and Care Research Health Technology Assessment Programme.

Calcium supplementation to prevent pre-eclampsia: protocol for an individual participant data meta-analysis, network meta-analysis and health economic evaluation

IntroductionLow dietary calcium intake is a risk factor for pre-eclampsia, a major contributor to maternal and perinatal mortality and morbidity worldwide. Calcium supplementation can prevent pre-eclampsia in women with low...

Digital cognitive–behavioural therapy to reduce suicidal ideation and behaviours: a systematic review and meta-analysis of individual participant data

QuestionDigital interventions based on cognitive–behavioural therapy (iCBT) is associated with reductions in suicidal ideation. However, fine-grained analyses of effects and potential effect-moderating variables are missing. This study aimed to investigate...

Efficacy and moderators of cognitive therapy versus behavioural activation for adults with depression: study protocol of a systematic review and meta-analysis of individual participant data.

Cognitive therapy and behavioural activation are both widely applied and effective psychotherapies for depression, but it is unclear which works best for whom. Individual participant data (IPD) meta-analysis allows for examining moderators at the participant level and can provide more precise effect estimates than conventional meta-analysis, which is based on study-level data. This article describes the protocol for a systematic review and IPD meta-analysis that aims to compare the efficacy of cognitive therapy and behavioural activation for adults with depression, and to explore moderators of treatment effect. (PROSPERO: CRD42022341602). Systematic literature searches will be conducted in PubMed, PsycINFO, EMBASE and the Cochrane Library, to identify randomised clinical trials comparing cognitive therapy and behavioural activation for adult acute-phase depression. Investigators of these trials will be invited to share their participant-level data. One-stage IPD meta-analyses will be conducted with mixed-effects models to assess treatment effects and to examine various available demographic, clinical and psychological participant characteristics as potential moderators. The primary outcome measure will be depressive symptom level at treatment completion. Secondary outcomes will include post-treatment anxiety, interpersonal functioning and quality of life, as well as follow-up outcomes. To the best of our knowledge, this will be the first IPD meta-analysis concerning cognitive therapy versus behavioural activation for adult depression. This study has the potential to enhance our knowledge of depression treatment by using state-of-the-art statistical techniques to compare the efficacy of two widely used psychotherapies, and by shedding more light on which of these treatments might work best for whom.

Health Insurance Coverage In Low- And Middle-Income Countries Remains Far From The Goal Of Universal Coverage.

This study aimed to determine levels of health insurance coverage in low- and middle-income countries and how coverage varies by people's sociodemographic characteristics. We conducted a population size-weighted, one-stage individual participant data meta-analysis of health insurance coverage, using a population-based sample of 2,035,401 participants ages 15-59 from nationally representative household surveys in fifty-six countries during the period 2006-18. One in five people (20.3percent) across the fifty-six countries in our study had health insurance. Health insurance coverage exceeded 50percent in only seven countries and 70percent in only three countries. Substantially more people had public health insurance than private health insurance (71.4percent versus 28.6percent). We found that men and older, more educated, and wealthier people were more likely to have health insurance; these sociodemographic gradients in health insurance coverage were strongest in sub-Saharan Africa and followed traditional lines of privilege. Low- and middle-income countries need to massively expand health insurance coverage if they intend to use insurance to achieve universal health coverage.

Scalable psychological interventions for Syrian refugees in Europe and the Middle East: STRENGTHS study protocol for a prospective individual participant data meta-analysis

IntroductionThe World Health Organization’s (WHO) scalable psychological interventions, such as Problem Management Plus (PM+) and Step-by-Step (SbS) are designed to be cost-effective non-specialist delivered interventions to reduce symptoms of common...

IDF21-0652 Blood pressure-lowering for prevention of major cardiovascular diseases in persons with and without type 2 diabetes

Background: There is insufficient randomised evidence as to whether the effect of blood pressure (BP)-lowering treatment differs in people with type 2 diabetes versus those without this metabolic condition, particularly at a normal or high-normal BP level. Aim: To investigate the effects of BP-lowering treatment on the risk of major cardiovascular events in people with and without type 2 diabetes, and by baseline levels of systolic and diastolic BP. Method: We used the resource provided by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) to conduct a one-stage individual participant data meta-analysis of major randomised trials. The primary outcome was total major cardiovascular events, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal myocardial infarction, and heart failure causing death or requiring hospitalisation. The analysis was stratified for type 2 diabetes status at baseline, and baseline categories of systolic BP (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg) and diastolic BP from <70 mm Hg to ≥110 mm Hg diastolic). Cox proportional hazard model stratified by the trial was used to estimate hazard ratio (HR). A Poisson regression model with an identity link was used to calculate the absolute risk reduction (ARR). Results: Data for 358,533 participants (58.4% men) from 51 randomised clinical trials were included in the analysis, in which 28.8% (n=103,325) of the participants had diagnosis of type 2 diabetes at baseline. Baseline mean systolic/diastolic BPs were 149/84 mm Hg in participants with type 2 diabetes (n=103,325) and 153/88 mm Hg in participants without type 2 diabetes (n=255,208). The incidence risks of primary events during the study follow-up time in participants with and without type 2 diabetes were 16.5% and 10.2%, respectively. Over 4.2 years of median follow-up, a fixed value of 5-mm Hg reduction in systolic BP was associated with a lower risk of major cardiovascular events both in participants with type 2 diabetes (HR 0.94 [95% CI 0.91 to 0.98]; ARR -0.015 [95% CI -0.020 to -0.010]) and in those without history of type 2 diabetes (HR 0.89 [95% CI 0.87 to 0.92]; ARR =-0.016 [95% CI -0.018 to -0.013]). In stratified analyses, we did not find reliable evidence for heterogeneity of treatment effects by baseline systolic or diastolic BP level in participants with or without type 2 diabetes (all P for interaction > 0.78). Discussion: The effect of BP reduction for primary and secondary prevention of major cardiovascular events was broadly comparable among people with and without type 2 diabetes, with no clinically important evidence that the level of systolic or diastolic BP at baseline is a determinant of treatment effect. Recommendations by guidelines on different BP reduction treatment in people with and without diabetes, or initiation of BP reduction therapy at a specific BP threshold, are not substantiated by these findings. This work will be presented on behalf of the Blood Pressure Lowering Treatment Trialists' Collaboration. Working group: Milad Nazarzadeh, Zeinab Bidel, Dexter Canoy, Emma Copland, Abbas Dehghan, Derrick A Bennett, George Davey Smith, Rury R. Holman, Mark Woodward, Ajay Gupta, Amanda Adler, Naveed Sattar, Richard J McManus, Koon Teo, Barry R Davis, John Chalmers, Carl J. Pepine, Kazem Rahimi.

Expectations for Return to Work Predict Return to Work in Workers with Low Back Pain: An Individual Participant Data (IPD) Meta-Analysis.

Purpose Low back pain is associated with disability and lost productivity due to inability of workers to return to work. Personal recovery expectation beliefs may be associated with return to work outcomes in those with low back pain at high risk for chronic disability. We aimed to (1) assess whether workers' expectations for return to work, following a low back pain episode, are associated with subsequent return to work; and (2) explore the relationships between return to work expectations and other prognostic factors in their association with work outcomes.Methods We conducted an Individual Participant Data (IPD) meta-analysis using data from five prospective cohort studies identified by a Cochrane prognostic factor review. A one-stage IPD meta-analysis approach was applied. Multi-level mixed effects models were used to determine the unadjusted and adjusted associations between expectations and return to work (logistic regression) and time to return to work (parametric survival models with Weibull distribution).Results The final dataset included 2302 participants. Positive expectations for return to work were associated with return to work at follow-up in both unadjusted (Odds Ratio (OR) 2.95; 95% Confidence Interval (CI) 2.21, 3.95) (n = 2071) and comprehensively adjusted (OR 2.01; 95% CI 1.46, 2.77) (n = 1109) models. Similar findings were identified for shorter length of time to return to work in both unadjusted (HR 2.40; 95% CI 2.09, 2.75) (n = 1156) and minimally adjusted (HR 2.43; 95% CI 2.12, 2.79) (n = 1154) models.Conclusions Results suggest workers with low expectations for return to work are at increased risk for long-term work disability.

Mathematical performance in childhood and early adult outcomes after very preterm birth: an individual participant data meta-analysis.

To investigate the strength of the independent associations of mathematics performance in children born very preterm (<32wks' gestation or <1500g birthweight) with attending postsecondary education and their current employment status in young adulthood. We harmonized data from six very preterm birth cohorts from five different countries and carried out one-stage individual participant data meta-analyses (n=954, 52% female) using mixed effects logistic regression models. Mathematics scores at 8 to 11 years of age were z-standardized using contemporary cohort-specific controls. Outcomes included any postsecondary education, and employment/education status in young adulthood. All models were adjusted for year of birth, gestational age, sex, maternal education, and IQ in childhood. Higher mathematics performance in childhood was independently associated with having attended any postsecondary education (odds ratio [OR] per SD increase in mathematics z-score: 1.36 [95% confidence interval {CI}: 1.03, 1.79]) but not with current employment/education status (OR 1.14 per SD increase [95% CI: 0.87, 1.48]). Among populations born very preterm, childhood mathematics performance is important for adult educational attainment, but not for employment status.

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis

SummaryBackgroundBlood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials.MethodsWe performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists’ Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons.Findings145 939 participants (88 500 [60·6%] men and 57 429 [39·4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4·5 years (IQR 2·0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0·89 [95% CI 0·84–0·95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0·84 [95% 0·76–0·93]) and angiotensin II receptor blockers (RR 0·84 [0·76–0·92]) reduced the risk of new-onset type 2 diabetes; however, the use of β blockers (RR 1·48 [1·27–1·72]) and thiazide diuretics (RR 1·20 [1·07–1·35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1·02 [0·92–1·13]).InterpretationBlood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes.FundingBritish Heart Foundation, National Institute for Health Research, and Oxford Martin School.

Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports

BackgroundSchizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries).MethodsWe searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556.ResultsOf the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference − 5.83, 95% CI − 10.79 to − 0.87, I2 = 8.5%, n = 4 studies, 1131 participants), Paliperidone (− 6.01, 95% CI − 8.7 to − 3.32, I2 = 4.3%, n = 13, 3821) and Paliperidone palmitate (− 7.89, 95% CI − 12.1 to − 3.69, I2 = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity.ConclusionIPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.

Blood pressure-lowering treatment for the prevention of cardiovascular events in patients with atrial fibrillation: An individual participant data meta-analysis.

Randomised evidence on the efficacy of blood pressure (BP)-lowering treatment to reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effects of BP-lowering drugs in patients with and without AF at baseline. The study was based on the resource provided by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), in which individual participant data (IPD) were extracted from trials with over 1,000 patient-years of follow-up in each arm, and that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs versus placebo, or more versus less intensive BP-lowering regimens. For this study, only trials that had collected information on AF status at baseline were included. The effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline were estimated using fixed-effect one-stage IPD meta-analyses based on Cox proportional hazards models stratified by trial. Furthermore, to assess whether the associations between the intensity of BP reduction and cardiovascular outcomes are similar in those with and without AF at baseline, we used a meta-regression. From the full BPLTTC database, 28 trials (145,653 participants) were excluded because AF status at baseline was uncertain or unavailable. A total of 22 trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Risk of bias assessment showed that 20 trials were at low risk of bias and 2 trials at moderate risk. Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering in patients with and without AF at baseline. Over 4.5 years of median follow-up, a 5-mm Hg systolic BP (SBP) reduction lowered the risk of major cardiovascular events both in patients with AF (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83 to 1.00) and in patients without AF at baseline (HR 0.91, 95% CI 0.88 to 0.93), with no difference between subgroups. There was no evidence for heterogeneity of treatment effects by baseline SBP or drug class in patients with AF at baseline. The findings of this study need to be interpreted in light of its potential limitations, such as the limited number of trials, limitation in ascertaining AF cases due to the nature of the arrhythmia and measuring BP in patients with AF. In this meta-analysis, we found that BP-lowering treatment reduces the risk of major cardiovascular events similarly in individuals with and without AF. Pharmacological BP lowering for prevention of cardiovascular events should be recommended in patients with AF.

Levothyroxine Treatment and Cardiovascular Outcomes in Older People With Subclinical Hypothyroidism: Pooled Individual Results of Two Randomised Controlled Trials.

BackgroundThe cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD).ObjectiveTo determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.MethodsCombined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism – a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age.ResultsThe median [IQR] age was 75.0 [69.7–81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41–1.25]), atrial fibrillation (HR 0.69 [0.32–1.52]), or heart failure (0.41 [0.13–1.35]), or all-cause mortality (HR 1.28 [0.54–3.03]), irrespective of history of CVD and age.ConclusionTreatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age.Clinical Trial Registration [ClinicalTrials.gov], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+).

BLOOD PRESSURE LOWERING TREATMENT FOR PREVENTION OF CARDIOVASCULAR EVENTS IN PATIENTS WITH ATRIAL FIBRILLATION: AN INDIVIDUAL-PARTICIPANT DATA META-ANALYSIS

Objective: Randomised evidence showing that pharmacological blood pressure (BP) lowering can reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effect of BP-lowering treatment on fatal and non-fatal cardiovascular outcomes in patients with and without AF. Design and method: We extracted individual participant data from all trials with over 1,000 person-years of follow-up that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs vs placebo, or to more vs less intensive BP-lowering regimens. We investigated the effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline using fixed-effect one-stage individual participant data meta-analyses based on Cox proportional hazards models stratified by trial. Results: Twenty-two trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Patients with AF had lower BP at baseline than patients without AF (143/84 mmHg, SD 21/12mmHg) versus 155/88 mmHg, SD 21/13 mmHg, respectively). Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering, both in patients with and without AF. The hazard ratio for major cardiovascular events was 0.91 in patients with AF (95% confidence interval [0.83 – 1.00]) and 0.91 without AF (95% confidence interval [0.88 – 0.93]) for each 5-mmHg reduction in systolic BP, with no difference between subgroups (p = 0.91) (Figure). Similar patterns were observed for individual components of the composite primary outcome. In patients with AF, there was no evidence that treatment effects varied according to baseline systolic BP or use of specific drug classes. Conclusions: BP-lowering treatment reduces the risk of major cardiovascular events in patients with AF to a similar extent to that of patients without AF, even when baseline BP is below recommended treatment thresholds. Owing to their higher absolute cardiovascular risk, treatment in patients with AF is likely to result in greater absolute risk reduction than in patients without AF. Guidelines should be updated to clearly recommend pharmacological BP lowering for prevention of cardiovascular events in patients with AF.

Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis.

SummaryBackgroundSome studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials.MethodsWe searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283).Findings33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4·2 years (IQR 3·0–5·0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0·99 [95% CI 0·95–1·04] for ACEIs; 0·96 [0·92–1·01] for ARBs; 0·98 [0·89–1·07] for β blockers; 1·01 [0·95–1·07] for thiazides), with the exception of calcium channel blockers (1·06 [1·01–1·11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1·00 [95% CI 0·93–1·09] for ACEIs; 0·99 [0·92–1·06] for ARBs; 0·99 [0·89–1·11] for β blockers; 1·04 [0·96–1·13] for calcium channel blockers; 1·00 [0·90–1·10] for thiazides).InterpretationWe found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers.FundingBritish Heart Foundation, National Institute for Health Research, Oxford Martin School.