Lipid-Lowering Trials Are Not Representative of Patients Managed in Clinical Practice: A Systematic Review and Meta-Analysis of Exclusion Criteria.

Background Randomized clinical trials (RCTs) might not be representative of the real-world population because of unreasonable exclusion criteria. We sought to determine which groups of patients are excluded from RCTs that included lipid-lowering therapy. Methods and Results We retrieved all trials from the Cholesterol Treatment Trialists Collaboration and systematically searched for large (≥1000 participants) lipid-lowering therapy RCTs, defined as statins, ezetimibe, and PCSK9 inhibitors. We predefined groups: older adults (>70 or >75 years), women, non-Whites, chronic kidney failure, heart failure, immunosuppression, cancer, dementia, treated thyroid disease, chronic obstructive pulmonary disease, mental illness, atrial fibrillation, multimorbidity (≥2 chronic diseases), and polypharmacy. We counted the number of RCTs excluding patients of the predefined groups and meta-analyzed the prevalence of included patients to obtain pooled estimates with a random-effects model. We included 42 RCTs (298 605 patients). Eighty-one percent of trials excluded patients with severe and 76% those with moderate kidney failure. Seventy-one percent of trials excluded groups of women, 64% excluded patients with moderate to severe heart failure, 64% those with immunosuppressant conditions, 48% those with cancer, 29% those with dementia, and 29% of trials excluded older adults. The pooled prevalence for patients >70 years of age was 25% (95% CI, 0%-49%), 11% (3%-18%) for >75 years of age, and 51% (38%-63%) for multimorbidity. Conclusions The majority of lipid-lowering therapy trials excluded patients with common diseases, such as moderate-to-severe kidney disease or heart failure or with immunosuppression. Underrepresenting certain populations, including women and older adults, might lead to limited transportability of study results and uncertainty on possible side-effects and efficacy in these groups. Future trials should promote diversity in the recruitment strategies and improve equity in cardiovascular research. Registration URL: ClinicalTrials.gov; Unique Identifier: CRD42021253909

Prevalence of co-occurring conditions in children and adults with autism spectrum disorder: A systematic review and meta-analysis.

This systematic review estimates the prevalence of co-occurring conditions (CCs) in children and adults with autism. A comprehensive search strategy consulting existing guidelines, diagnostic manuals, experts, carers, and autistic people was developed. PubMed and PsycInfo databases from inception to May 2022 were searched. PROSPERO registration: CRD42019132347. Two blind authors screened and extracted the data. Prevalence estimates for different CCs were summarized by using random effects models. Subgroup analyses were performed for age groups (children/adolescents vs adults) and study designs (population/registry-based vs clinical sample-based). Of 19,932 studies, 340 publications with about 590,000 participants were included and meta-analyzed to estimate the prevalence of 38-point prevalence, 27-lifetime, and 3 without distinction between point and lifetime prevalence. Point prevalence of developmental coordination disorder, sleep-wake problem, gastrointestinal problem, ADHD, anxiety disorder, overweight/obesity, feeding and eating disorder, elimination disorder, disruptive behavior, and somatic symptoms and related disorder were the most frequent CCs. Prevalence differed depending on the age group and study design. Knowing specific CCs linked to autism helps professional investigations and interventions for improved outcomes

The predicted probability of live birth in In Vitro Fertilization varies during important stages throughout the treatment: analysis of 114,882 first cycles.

RESEARCH QUESTION How much the variability in patients' response during in vitro fertilization (IVF) may add to the initial predicted prognosis based only on patients' basal characteristics? DESIGN Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). Data involving 114,882 stimulated fresh IVF cycles were retrospectively analyzed. Logistic regression was used to develop the models. RESULTS Prediction of live birth was feasible with moderate accuracy in all of the three models; discrimination of the model based only on basal patients' characteristics (AUROC 0.61) was markedly improved adding information of number of embryos (AUROC 0.65) and, mostly, number of oocytes (AUROC 0.66). CONCLUSIONS The addition to prediction models of parameters such as the number of embryos obtained and especially the number of oocytes retrieved can statistically significantly improve the overall prediction of live birth probabilities when based on only basal patients' characteristics. This seems to be particularly true for women after the first IVF cycle. Since ovarian response affects the probability of live birth in IVF, it is highly recommended to add markers of ovarian response to models based on basal characteristics to increase their predictive ability

Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis.

BACKGROUND: Dysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer's disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments are not currently used in clinical practice. OBJECTIVE: To assess the efficacy of drugs with principally noradrenergic action in improving cognitive and neuropsychiatric symptoms in Alzheimer's disease. METHODS: The MEDLINE, Embase and ClinicalTrials.gov databases were searched from 1980 to December 2021. We generated pooled estimates using random effects meta-analyses. RESULTS: We included 19 randomised controlled trials (1811 patients), of which six were judged as 'good' quality, seven as 'fair' and six 'poor'. Meta-analysis of 10 of these studies (1300 patients) showed a significant small positive effect of noradrenergic drugs on global cognition, measured using the Mini-Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale (standardised mean difference (SMD): 0.14, 95% CI: 0.03 to 0.25, p=0.01; I2=0%). No significant effect was seen on measures of attention (SMD: 0.01, 95% CI: -0.17 to 0.19, p=0.91; I2=0). The apathy meta-analysis included eight trials (425 patients) and detected a large positive effect of noradrenergic drugs (SMD: 0.45, 95% CI: 0.16 to 0.73, p=0.002; I2=58%). This positive effect was still present following removal of outliers to account for heterogeneity across studies. DISCUSSION: Repurposing of established noradrenergic drugs is most likely to offer effective treatment in Alzheimer's disease for general cognition and apathy. However, several factors should be considered before designing future clinical trials. These include targeting of appropriate patient subgroups and understanding the dose effects of individual drugs and their interactions with other treatments to minimise risks and maximise therapeutic effects. PROSPERO REGISTERATION NUMBER: CRD42021277500

Is there a shift from cardiovascular to cancer death in lipid-lowering trials? A systematic review and meta-analysis.

BackgroundLipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk.MethodsWe performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs.ResultsWe included 27 trials with 188'259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97-1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00-1.23), while the RR for CV death was 0.96 (0.91-1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99-1.47).ConclusionLLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations.Prospero registrationCRD42021271658

S1 Dataset -

BackgroundLipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk.MethodsWe performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs.ResultsWe included 27 trials with 188’259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97–1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00–1.23), while the RR for CV death was 0.96 (0.91–1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99–1.47).ConclusionLLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations.PROSPERO registrationCRD42021271658</div

Search strategy.

BackgroundLipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk.MethodsWe performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs.ResultsWe included 27 trials with 188’259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97–1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00–1.23), while the RR for CV death was 0.96 (0.91–1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99–1.47).ConclusionLLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations.PROSPERO registrationCRD42021271658</div

Baseline characteristics.

LLT = Lipid-lowering treatment, CV = cardiovascular. (DOCX)</p

Relative risk for cancer mortality according to lipid-lowering therapy and the prevalence of participants aged ≥75 years^{1 1}.

The SPARCL and REPRIEVE trial did not report the prevalence of participants aged ≥75 years pts = participants, CI = confidence interval.</p