Quantitative assessment of baseline imbalances in evolocumab and alirocumab trials: a meta-epidemiological study.

BACKGROUND: Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials. METHODS: We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined. RESULTS: We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04). CONCLUSIONS: Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.

Efficacy of antipsychotics in dementia depended on the definition of patients and outcomes: a meta-epidemiological study.

OBJECTIVES: Postulating that efficacy of antipsychotics for agitation and psychosis in dementia is best estimated in trials among patients with these symptoms and with symptom-specific outcomes, we investigated whether clinically broader definitions affected the pooled efficacy. STUDY DESIGN AND SETTING: Trials were searched in multiple databases and categorized according to patient population (agitated, psychotic, and mixed) and outcome scale (agitation, psychosis, and generic). Standardized mean differences with 95% confidence intervals were calculated for conventional and atypical antipsychotics separately. RESULTS: Thirty trials met our inclusion criteria. Conventional antipsychotics might have a small effect in agitated patients on agitation scales (-0.44, -0.88, 0.01) and in psychotic patients on psychosis scales (-0.31, -0.61, -0.02). There was no effect on generic scales. Efficacy of atypical antipsychotics was not established in agitated patients on agitation scales (-0.15, -0.43, 0.13) and in psychotic patients on psychosis scales (-0.11, -0.20, -0.03) but was small in mixed patients on agitation scales (-0.29, -0.40, -0.18). CONCLUSION: Pooled efficacy of antipsychotics for agitation and psychosis in dementia is biased when based on trials that included patients without these target symptoms or on results measured with generic scales. This finding is important for reviewers and guideline developers who select trials for reviews.

Attention, arousal and other rapid bedside screening instruments for delirium in older patients: a systematic review of test accuracy studies.

Objective: delirium occurs frequently in frail patients but is easily missed. Screening with a rapid, easy-to-use and highly sensitive instrument might help improve recognition. The aim of this study was to review attention, arousal and other rapid bedside screening instruments for delirium in older patients. Methods: a literature search was performed in PubMed, PsycINFO and Embase. We scrutinized forward citations in Google Scholar, and references of included articles and prior reviews. We included studies among older patients that investigated the sensitivity and specificity of delirium screening instruments that could be administered in 3 min or less, and did not require surrogate information. We extracted study characteristics, risk of bias, sensitivity and specificity. Results: we identified 27 studies among 4,766 patients in hospitals and nursing homes. They tested many different single and several combined screening instruments. Prevalence of delirium varied between 4% and 57%. Only one study scored a low risk of bias on all domains. Sensitivity varied between 17% and 100%, and specificity between 38% and 99%. Of the 22 tests with sensitivity ≥90%, seven also had specificity ≥80% in older patients in general. These results were approximately reproduced for the Observational Scale of Level of Arousal (OSLA) and Richmond Agitation and Sedation Scale (RASS): sensitivity and specificity were >80%. Conclusion: two arousal tests-OSLA and RASS-had reproduced high sensitivity and specificity in older patients. Nurses can administer these tests during daily interaction with patients. Test accuracy studies about rapid screening tools for delirium superimposed on dementia were scarce.

[Revised practice guidelines 'Delirium in adults and the elderly']. / Herziene richtlijn 'Delier volwassenen en ouderen'.

A multidisciplinary workgroup has revised the 2004 practice guidelines on 'Delirium' on the initiative of the Dutch Geriatrics Society. In comparison with the previous version, the new guidelines place more emphasis on screening and non-pharmaceutical prevention and treatment. They recommend a degree of restraint when prescribing medication. Both the patient's and the caregiver's perspectives are discussed. The guidelines also focus on delirium in patients in a nursing home setting, and describe what the workgroup regards as optimal care for patients suffering from delirium. The revised guidelines consider the diagnosis and treatment of delirium as a part of basic medical care and primarily the responsibility of the attending physician. The workgroup advises consulting an expert in the field of delirium only in cases of lack of experience, and for complex cases. The guidelines also include recommendations for the organization of follow-up care for the delirium patient.

The effect of common genetic variation in 11ß-hydroxysteroid dehydrogenase type 1 on hypothalamic-pituitary-adrenal axis activity and incident depression.

BACKGROUND: Accumulating evidence suggests that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) is involved in depression. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) converts inert cortisone to active cortisol and is implicated in HPA axis regulation in animal studies. The aim of our study was to identify polymorphisms in 11ß-HSD1 gene (HSD11B1) with consistent associations with increased HPA axis activity and relate those polymorphisms to depression. METHODS: Twelve single-nucleotide polymorphisms (SNPs), including 11 tagging SNPs, were selected using the HapMap database and genotyped in 4228 participants of the population-based Rotterdam Study. The outcome measures were salivary cortisol levels after awakening, 30 min later, at 1700 h, at bedtime, and plasma levels of androstenedione (in women only). SNPs that were significantly associated with cortisol as well as androstenedione levels were also related to incident depression. RESULTS: rs11119328 was associated with higher cortisol saliva samples collected at bedtime as well as higher androstenedione levels (P value after correction for multiple testing: 0.01 and 0.04, respectively). Carriers of this polymorphism had an increased risk of an incident depression (hazard ratio 1.28, 95% confidence interval 1.03-1.59). Two other SNPs, which were in high linkage disequilibrium with rs11119328, were related to higher cortisol levels but not with androstenedione levels. CONCLUSIONS: We identified one SNP, which was associated with increased salivary cortisol levels at nadir as well as higher androstenedione levels. Moreover, this SNP was also associated with a higher risk of an incident depression. This suggests that 11ß-HSD1 is implicated in human HPA axis regulation and susceptibility to depression.

Cerebrovascular risk factors and incident depression in community-dwelling elderly.

OBJECTIVE: The 'vascular depression' hypothesis suggests that late-life depression results from vascular brain damage. We studied the longitudinal association between cerebrovascular risk factors and incident depression in a large population-based study. METHOD: Two thousand nine hundred and thirty-one persons with the age of > or =61 years were followed up. Data on a comprehensive set of cerebrovascular risk factors were collected at baseline. Participants received a psychiatric assessment 5 years later to establish DSM-IV diagnoses. RESULTS: Only current smoking and antihypertensive drug use were independently associated with incident depressive symptoms. Diabetes mellitus and the Framingham stroke risk score were related to incident depressive disorder. No relation with depression was observed for cholesterol, diastolic and systolic blood pressure, history of cardiovascular disease, atrial fibrillation, left ventricular hypertrophy or the use of statins and anticoagulants. CONCLUSION: These results moderately support the 'vascular depression' hypothesis.