The Role of Point-of-Care C-Reactive Protein Testing in Antibiotic Prescribing for Respiratory Tract Infections: A Survey among Swiss General Practitioners.

Understanding the decision-making strategies of general practitioners (GPs) could help reduce suboptimal antibiotic prescribing. Respiratory tract infections (RTIs) are the most common reason for inappropriate antibiotic prescribing in primary care, a key driver of antibiotic resistance (ABR). We conducted a nationwide prospective web-based survey to explore: (1) The role of C-reactive protein (CRP) point-of-care testing (POCT) on antibiotic prescribing decision-making for RTIs using case vignettes; and (2) the knowledge, attitudes and barriers/facilitators of antibiotic prescribing using deductive analysis. Most GPs (92-98%) selected CRP-POCT alone or combined with other diagnostics. GPs would use lower CRP cut-offs to guide prescribing for (more) severe RTIs than for uncomplicated RTIs. Intermediate CRP ranges were significantly wider for uncomplicated than for (more) severe RTIs (p = 0.001). Amoxicillin/clavulanic acid was the most frequently recommended antibiotic across all RTI case scenarios (65-87%). Faced with intermediate CRP results, GPs preferred 3-5-day follow-up to delayed prescribing or other clinical approaches. Patient pressure, diagnostic uncertainty, fear of complications and lack of ABR understanding were the most GP-reported barriers to appropriate antibiotic prescribing. Stewardship interventions considering CRP-POCT and the barriers and facilitators to appropriate prescribing could guide antibiotic prescribing decisions at the point of care.

Time Trends and Factors Associated with Antibiotic Prescribing in Swiss Primary Care (2008 to 2020).

Antibiotic resistance (ABR) is a major threat to public health, and the majority of antibiotics are prescribed in the outpatient setting, especially in primary care. Monitoring antibiotic consumption is one key measure in containing ABR, but Swiss national surveillance data are limited. We conducted a retrospective cross-sectional study to characterise the patterns of antibiotic prescriptions, assess the time trends, and identify the factors associated with antibiotic prescribing in Swiss primary care. Using electronic medical records data, we analysed 206,599 antibiotic prescriptions from 112,378 patients. Based on 27,829 patient records, respiratory (52.1%), urinary (27.9%), and skin (4.8%) infections were the commonest clinical indications for antibiotic prescribing. The most frequently prescribed antibiotics were broad-spectrum penicillins (BSP) (36.5%), fluoroquinolones (16.4%), and macrolides/lincosamides (13.8%). Based on the WHO AWaRe classification, antibiotics were 57.9% Core-Access and 41.7% Watch, 69% of which were quinolones and macrolides. Between 2008 and 2020, fluoroquinolones and macrolides/lincosamides prescriptions significantly declined by 53% and 51%; BSP prescriptions significantly increased by 54%. Increasing patients' age, volume, and employment level were significantly associated with antibiotic prescribing. Our results may inform future antibiotic stewardship interventions to improve antibiotic prescribing.

Point-of-Care C-Reactive Protein Testing to Reduce Antibiotic Prescribing for Respiratory Tract Infections in Primary Care: Systematic Review and Meta-Analysis of Randomised Controlled Trials.

C-reactive protein (CRP) point-of-care testing (POCT) is increasingly being promoted to reduce diagnostic uncertainty and enhance antibiotic stewardship. In primary care, respiratory tract infections (RTIs) are the most common reason for inappropriate antibiotic prescribing, which is a major driver for antibiotic resistance. We systematically reviewed the available evidence on the impact of CRP-POCT on antibiotic prescribing for RTIs in primary care. Thirteen moderate to high-quality studies comprising 9844 participants met our inclusion criteria. Meta-analyses showed that CRP-POCT significantly reduced immediate antibiotic prescribing at the index consultation compared with usual care (RR 0.79, 95%CI 0.70 to 0.90, p = 0.0003, I2 = 76%) but not during 28-day (n = 7) follow-up. The immediate effect was sustained at 12 months (n = 1). In children, CRP-POCT reduced antibiotic prescribing when CRP (cut-off) guidance was provided (n = 2). Meta-analyses showed significantly higher rates of re-consultation within 30 days (n = 8, 1 significant). Clinical recovery, resolution of symptoms, and hospital admissions were not significantly different between CRP-POCT and usual care. CRP-POCT can reduce immediate antibiotic prescribing for RTIs in primary care (number needed to (NNT) for benefit = 8) at the expense of increased re-consultations (NNT for harm = 27). The increase in re-consultations and longer-term effects of CRP-POCT need further evaluation. Overall, the benefits of CRP-POCT outweigh the potential harms (NNTnet = 11).

Toward Standardized Monitoring of Patients With Chronic Diseases in Primary Care Using Electronic Medical Records: Development of a Tool by Adapted Delphi Procedure.

BACKGROUND: Long-term care for patients with chronic diseases poses a huge challenge in primary care. There are deficits in care, especially regarding monitoring and creating structured follow-ups. Appropriate electronic medical records (EMR) could support this, but so far, no generic evidence-based template exists. OBJECTIVE: The aim of this study is to develop an evidence-based standardized, generic template that improves the monitoring of patients with chronic conditions in primary care by means of an EMR. METHODS: We used an adapted Delphi procedure to evaluate a structured set of evidence-based monitoring indicators for 5 highly prevalent chronic diseases (ie, diabetes mellitus type 2, asthma, arterial hypertension, chronic heart failure, and osteoarthritis). We assessed the indicators' utility in practice and summarized them into a user-friendly layout. RESULTS: This multistep procedure resulted in a monitoring tool consisting of condensed sets of indicators, which were divided into sublayers to maximize ergonomics. A cockpit serves as an overview of fixed goals and a set of procedures to facilitate disease management. An additional tab contains information on nondisease-specific indicators such as allergies and vital signs. CONCLUSIONS: Our generic template systematically integrates the existing scientific evidence for the standardized long-term monitoring of chronic conditions. It contains a user-friendly and clinically sensible layout. This template can improve the care for patients with chronic diseases when using EMRs in primary care.

Shared decision making for men facing prostate cancer treatment: a systematic review of randomized controlled trials.

Aims: To synthesize the empirical evidence on the effectiveness of shared decision making (SDM) compared to usual care for prostate cancer (PC) treatment. Methods and results: A systematic review of academic (MEDLINE, EMBASE, Cochrane Library, CINHAL, PsychINFO, and Scopus) and grey (clinicaltrials.gov, WHO trial search, meta-Register ISRCTN, Google Scholar, opengrey, and ohri.ca) literature, also identified from contacting authors and hand-searching bibliographies. We included randomized controlled trials (RCTs): 1) comparing SDM to usual care for decisions about PC treatment, 2) conducted in primary or specialized care, 3) fulfilling the key SDM features, and 4) reporting quantitative outcome data. Four RCTs from Canada (n=3) and the USA were included and comprised 1,065 randomized men, most (89.8%) of whom were in PC stage T1-T2. The studies reported 24 outcome measures. In 62.5% study estimates, SDM was similar to usual care at improving patient satisfaction and mood, and at reducing decisional conflict and decisional regret. In 37.5% study estimates, SDM significantly improved knowledge, perception of being informed and patient-perceived quality of life (QoL) at four weeks. There was a dearth of outcome data, particularly on the adherence to treatment and on patient-important and clinically relevant health outcomes such as symptoms and mortality. Conclusion: SDM may positively influence men's knowledge and may have a positive but short-term effect on patient-perceived QoL. The (long-term) effects of SDM on patient-related outcomes for decisions about PC treatment are unclear. Future research needs consensus about the interventions and outcomes needed to evaluate SDM and should address the absence of evidence on health outcomes.

Toward Standardized Monitoring of Patients With Chronic Diseases in Primary Care Using Electronic Medical Records: Systematic Review.

BACKGROUND: Long-term care for patients with chronic diseases poses a huge challenge in primary care. In particular, there is a deficit regarding monitoring and structured follow-up. Appropriate electronic medical records (EMRs) could help improving this but, so far, there are no evidence-based specifications concerning the indicators that should be monitored at regular intervals. OBJECTIVE: The aim was to identify and collect a set of evidence-based indicators that could be used for monitoring chronic conditions at regular intervals in primary care using EMRs. METHODS: We searched MEDLINE (Ovid), Embase (Elsevier), the Cochrane Library (Wiley), the reference lists of included studies and relevant reviews, and the content of clinical guidelines. We included primary studies and guidelines reporting about indicators that allow for the assessment of care and help monitor the status and process of disease for five chronic conditions, including type 2 diabetes mellitus, asthma, arterial hypertension, chronic heart failure, and osteoarthritis. RESULTS: The use of the term "monitoring" in terms of disease management and long-term care for patients with chronic diseases is not widely used in the literature. Nevertheless, we identified a substantial number of disease-specific indicators that can be used for routine monitoring of chronic diseases in primary care by means of EMRs. CONCLUSIONS: To our knowledge, this is the first systematic review summarizing the existing scientific evidence on the standardized long-term monitoring of chronic diseases using EMRs. In a second step, our extensive set of indicators will serve as a generic template for evaluating their usability by means of an adapted Delphi procedure. In a third step, the indicators will be summarized into a user-friendly EMR layout.

Correction to: The effects of shared decision-making compared to usual care for prostate cancer screening decisions: a systematic review and meta-analysis.

Following publication of the original article [1], the authors notified us of a misleading data presentation in Table 4.

The effects of shared decision-making compared to usual care for prostate cancer screening decisions: a systematic review and meta-analysis.

BACKGROUND: Shared decision-making (SDM) is recommended for men facing prostate cancer (PC) screening decisions. We synthesize the evidence on the comparative effectiveness of SDM with usual care. METHODS: We searched academic and grey literature databases, and other sources for primary randomised controlled trials (RCTs) published in English comparing SDM to usual care and conducted in primary and specialised care. We assessed the individual study risk of bias, and calculated the study-specific and pooled relative risks (RR) or standardised mean differences (SMD) [with 95% confidence intervals (CI)] to perform random-effects meta-analyses for SDM-related and patient outcomes. RESULTS: Four RCTs comparing SDM to usual care, involving 1760 men, were included. SDM improved knowledge (SMD 0.23, 95%CI 0.02 to 0.43; 2 RCTs), but was not different to usual care in reducing either patient participation in prostate-specific antigen (PSA) testing (RR 1.03, 95%CI 0.90 to 1.19; 2 RCTs) or decisional conflict (SMD -0.04, 95%CI -0.23 to 0.15; SMD -0.05, 95%CI -0.24 to 0.14; 2 RCTs). Individual trial estimates (46.7%) also suggest that SDM may reduce or neutralise physicians' tendency for PSA screening, and may improve the accuracy of patients' perception of lifetime-risks and men's views towards screening. There was no evidence on the effects of SDM on health outcomes. The studies represent various interventions and outcomes and are prone to risk of bias. CONCLUSIONS: There is currently insufficient evidence to support a clear association of SDM on patient- and SDM-related outcomes for decisions about PSA testing. Further research needs to assess the clinical effectiveness of SDM using well-defined SDM interventions and outcomes. It should address the absence of evidence, particularly on health outcomes.

Shared decision-making for prostate cancer screening and treatment: a systematic review of randomised controlled trials.

INTRODUCTION: Men facing prostate cancer screening and treatment need to make critical and highly preference-sensitive decisions that involve a variety of potential benefits and risks. Shared decision-making (SDM) is considered fundamental for "preference-sensitive" medical decisions and it is guideline-recommended. There is no single definition of SDM however. We systematically reviewed the extent of SDM implementation in interventions to facilitate SDM for prostate cancer screening and treatment. METHODS: We searched Medline Ovid, Embase (Elsevier), CINHAL (EBSCOHost), The Cochrane Library (Wiley), PsychINFO (EBSCOHost), Scopus, clinicaltrials.gov, ISRCTN registry, the WHO search portal, ohri.ca, opengrey.eu, Google Scholar, and the reference lists of included studies, clinical guidelines and relevant reviews. We also contacted the authors of relevant abstracts without available full text. We included primary peer-reviewed and grey literature of randomised controlled trials (RCTs) reported in English, conducted in primary and specialised care, addressing interventions aiming to facilitate SDM for prostate cancer screening and treatment. Two reviewers independently selected studies, appraised interventions and assessed the extent of SDM implementation based on the key features of SDM, namely information exchange, deliberation and implementation. We considered bi-directional deliberation as a central and mandatory component of SDM. We performed a narrative synthesis. RESULTS: Thirty-six RCTs including 19 196 randomised patients met the eligibility criteria; they were mainly conducted in North America (n = 28). The median year of publication was 2008 (1997-2015). Twenty-three RCTs addressed decision-making for screening, twelve for treatment and one for both screening and treatment for prostate cancer. Bi-directional interactions between healthcare providers and patients were verified in 31 RCTs, but only 14 fulfilled the three key SDM features, 14 had at least "deliberation", one had "unclear deliberation" and two had no signs of deliberation. CONCLUSIONS: There is significant variation in the extent of SDM implementation among studies addressing SDM for prostate cancer screening and treatment. Further evaluation of these results on patient outcomes, a standardised SDM definition and guidance for an effective implementation in several clinical settings are needed.

The impact of interventions to improve the quality of prescribing and use of antibiotics in primary care patients with respiratory tract infections: a systematic review protocol.

INTRODUCTION: Respiratory tract infections (RTIs) are the most common reason for primary care (PC) consultations and for antibiotic prescribing and use. The majority of RTIs have a viral aetiology however, and antibiotic consumption is ineffective and unnecessary. Inappropriate antibiotic use contributes greatly to antibiotic resistance (ABR) leading to complications, increased adverse events, reconsultations and costs. Improving antibiotic consumption is thus crucial to containing ABR, which has become an urgent priority worldwide. We will systematically review the evidence about interventions aimed at improving the quality of antibiotic prescribing and use for acute RTI. METHODS AND ANALYSIS: We will include primary peer-reviewed and grey literature of studies conducted on in-hours and out-of-hours PC patients (adults and children): (1) randomised controlled trials (RCTs), quasi-RCTs and/or cluster-RCTs evaluating the effectiveness, feasibility and acceptability of patient-targeted and clinician-targeted interventions and (2) RCTs and other study designs evaluating the effectiveness of public campaigns and regulatory interventions. We will search MEDLINE (EBSCOHost), EMBASE (Elsevier), the Cochrane Library (Wiley), CINHAL (EBSCOHost), PsychINFO (EBSCOHost), Web of Science, LILACS (Latin American and Caribbean Literature on Health Sciences), TRIP (Turning Research Into Practice) and opensgrey.eu without language restriction. We will also search the reference lists of included studies and relevant reviews. Primary outcomes include the rates of (guideline-recommended) antibiotics prescribed and/or used. Secondary outcomes include immediate or delayed use of antibiotics, and feasibility and acceptability outcomes. We will assess study eligibility and risk of bias, and will extract data. Data permitting, we will perform meta-analyses. ETHICS AND DISSEMINATION: This is a systematic review protocol and so formal ethical approval is not required. We will not collect confidential, personal or primary data. The findings of this review will be disseminated at national and international scientific meetings. TRIAL REGISTRATION NUMBER: PROSPERO trial (CRD42017035305).

Task-Shifting From Physicians to Nurses in Primary Care and its Impact on Resource Utilization: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Task-shifting from physicians to nurses has gained increasing interest in health policy but little is known about its efficiency. This systematic review was conducted to compare resource utilization with task-shifting from physicians to nurses in primary care. Literature searches yielded 4,589 citations. Twenty studies comprising 13,171 participants met the inclusion criteria. Meta-analyses showed nurses had more return consultations and longer consultations than physicians but were similar in their use of referrals, prescriptions, or investigations. The evidence has limitations, but suggests that the effects may be influenced by the utilization of resources, context of care, available guidance, and supervision. Cost data suggest physician-nurse salary and physician's time spent on supervision and delegation are important components of nurse-led care costs. More rigorous research involving a wider range of nurses from many countries is needed reporting detailed accounts of nurses' roles and competencies, qualifications, training, resources, time available for consultations, and all-cause costs.

The effect of physician-nurse substitution in primary care in chronic diseases: a systematic review.

BACKGROUND: Chronically ill and ageing populations demand increasing human resources who can provide on-going and frequent follow-up care. We performed a systematic review to assess the effect of physician-nurse substitution on process care outcomes. METHODS: We searched OVID Medline, Embase, CINAHL and The Cochrane Library for all available dates up to August 2012 and updated in February 2014. We selected and critically appraised published randomised controlled trials (RCT) and followed the PRISMA guidelines for the reporting of systematic reviews. RESULTS: A total of 14 RCTs comprising 10,743 participants met the inclusion criteria. Studies were generally small and suffered from attrition of ≥20% and selection biases. There were 53 process measurements investigated in the 14 RCTs, many of which were unique to specific conditions. Accounts of nurses' roles, responsibilities, tasks, qualifications and training content/components were not described in sufficient detail. Most study estimates showed no significant differences between nurse-led care and physician-led care while less than a half (~40%) favoured nurse-led care. CONCLUSIONS: Despite the methodological limitations and the varying nurses' roles and competencies across studies, specially trained nurses can provide care that is at least as equivalent to care provided by physicians for the management of chronic diseases, in terms of process of care. Future, larger studies with better quality methods are needed and should report and assess whether the differences in effects vary due to diversity in roles, qualifications, training competencies and characteristics of clinicians delivering substitution of care.

Integrated care programmes for adults with chronic conditions: a meta-review.

OBJECTIVE: To review systematic reviews and meta-analyses of integrated care programmes in chronically ill patients, with a focus on methodological quality, elements of integration assessed and effects reported. DESIGN: Meta-review of systematic reviews and meta-analyses identified in Medline (1946-March 2012), Embase (1980-March 2012), CINHAL (1981-March 2012) and the Cochrane Library of Systematic Reviews (issue 1, 2012). MAIN OUTCOME MEASURES: Methodological quality assessed by the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) checklist; elements of integration assessed using a published list of 10 key principles of integration; effects on patient-centred outcomes, process quality, use of healthcare and costs. RESULTS: Twenty-seven systematic reviews were identified; conditions included chronic heart failure (CHF; 12 reviews), diabetes mellitus (DM; seven reviews), chronic obstructive pulmonary disease (COPD; seven reviews) and asthma (five reviews). The median number of AMSTAR checklist items met was five: few reviewers searched for unpublished literature or described the primary studies and interventions in detail. Most reviews covered comprehensive services across the care continuum or standardization of care through inter-professional teams, but organizational culture, governance structure or financial management were rarely assessed. A majority of reviews found beneficial effects of integration, including reduced hospital admissions and re-admissions (in CHF and DM), improved adherence to treatment guidelines (DM, COPD and asthma) or quality of life (DM). Few reviews showed reductions in costs. CONCLUSIONS: Systematic reviews of integrated care programmes were of mixed quality, assessed only some components of integration of care, and showed consistent benefits for some outcomes but not others.

Substitution of physicians by nurses in primary care: a systematic review and meta-analysis.

BACKGROUND: In many countries, substitution of physicians by nurses has become common due to the shortage of physicians and the need for high-quality, affordable care, especially for chronic and multi-morbid patients. We examined the evidence on the clinical effectiveness and care costs of physician-nurse substitution in primary care. METHODS: We systematically searched OVID Medline and Embase, The Cochrane Library and CINAHL, up to August 2012; selected and critically appraised published randomised controlled trials (RCTs) that compared nurse-led care with care by primary care physicians on patient satisfaction, Quality of Life (QoL), hospital admission, mortality and costs of healthcare. We assessed the individual study risk of bias, calculated the study-specific and pooled relative risks (RR) or standardised mean differences (SMD); and performed fixed-effects meta-analyses. RESULTS: 24 RCTs (38,974 participants) and 2 economic studies met the inclusion criteria. Pooled analyses showed higher overall scores of patient satisfaction with nurse-led care (SMD 0.18, 95% CI 0.13 to 0.23), in RCTs of single contact or urgent care, short (less than 6 months) follow-up episodes and in small trials (N ≤ 200). Nurse-led care was effective at reducing the overall risk of hospital admission (RR 0.76, 95% CI 0.64 to 0.91), mortality (RR 0.89, 95% CI 0.84 to 0.96), in RCTs of on-going or non-urgent care, longer (at least 12 months) follow-up episodes and in larger (N > 200) RCTs. Higher quality RCTs (with better allocation concealment and less attrition) showed higher rates of hospital admissions and mortality with nurse-led care albeit less or not significant. The results seemed more consistent across nurse practitioners than with registered or licensed nurses. The effects of nurse-led care on QoL and costs were difficult to interpret due to heterogeneous outcome reporting, valuation of resources and the small number of studies. CONCLUSIONS: The available evidence continues to be limited by the quality of the research considered. Nurse-led care seems to have a positive effect on patient satisfaction, hospital admission and mortality. This important finding should be confirmed and the determinants of this effect should be assessed in further, larger and more methodically rigorous research.

Effects of physician-nurse substitution on clinical parameters: a systematic review and meta-analysis.

BACKGROUND: Physicians' shortage in many countries and demands of high-quality and affordable care make physician-nurse substitution an appealing workforce strategy. The objective of this study is to conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the impact of physician-nurse substitution in primary care on clinical parameters. METHODS: We systematically searched OVID Medline and Embase, The Cochrane Library and CINAHL, up to August 2012; selected peer-reviewed RCTs comparing physician-led care with nurse-led care on changes in clinical parameters. Study selection and data extraction were performed in duplicate by independent reviewers. We assessed the individual study risk of bias; calculated the study-specific and pooled relative risks (RR) or weighted mean differences (WMD); and performed fixed-effects meta-analyses. RESULTS: 11 RCTs (N = 30,247) were included; most were from Europe, generally small with higher risk of bias. In all studies, nurses provided care for complex conditions including HIV, hypertension, heart failure, cerebrovascular diseases, diabetes, asthma, Parkinson's disease and incontinence. Meta-analyses showed greater reductions in systolic blood pressure (SBP) in favour of nurse-led care (WMD -4.27 mmHg, 95% CI -6.31 to -2.23) but no statistically significant differences between groups in the reduction of diastolic blood pressure (DBP) (WMD -1.48 mmHg, 95%CI -3.05 to -0.09), total cholesterol (TC) (WMD -0.08 mmol/l, 95%CI -0.22 to 0.07) or glycosylated haemoglobin (WMD 0.12%HbAc1, 95%CI -0.13 to 0.37). Of other 32 clinical parameters identified, less than a fifth favoured nurse-led care while 25 showed no significant differences between groups. LIMITATIONS: disease-specific interventions from a small selection of healthcare systems, insufficient quantity and quality of studies, many different parameters. CONCLUSIONS: trained nurses appeared to be better than physicians at lowering SBP but similar at lowering DBP, TC or HbA1c. There is insufficient evidence that nurse-led care leads to better outcomes of other clinical parameters than physician-led care.

Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic associations with CAA to better understand its pathogenesis. METHODS: We comprehensively sought and critically appraised published studies of associations between any genetic polymorphism and histopathologically confirmed CAA. We assessed the effects of genotype by calculating study specific and pooled odds ratios (ORs) in meta-analyses, and assessed small study bias. RESULTS: 58 studies (6855 participants) investigated apolipoprotein E (APOE) genotype and sporadic CAA. Meta-analysis of 24 (3520 participants) of these showed an association of APOE ε4 with CAA (ε4 present vs absent, pooled OR 2.7, 95% CI 2.3 to 3.1, p<0.00001), which was dose dependent, robust to potential small study biases and occurred irrespective of dementia status. There was no significant association between APOE ε2 and CAA. Among 24 studies (4703 participants) of other genetic polymorphisms, there was preliminary evidence of an association with CAA of polymorphisms in the transforming growth factor ß1 gene (two studies, 449 participants), translocase of outer mitochondrial membrane 40 gene (one study, 723 participants) and the complement component receptor 1 gene (one study, 544 participants). There were insufficient data to draw conclusions from 24 studies (∼200 participants) of APOE and hereditary CAA or familial Alzheimer's disease. CONCLUSIONS: There is convincing evidence for a dose dependent association between APOE ε4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA.

Association between apolipoprotein E genotype and carotid intima-media thickness may suggest a specific effect on large artery atherothrombotic stroke.

BACKGROUND AND PURPOSE: Apolipoprotein E genotype (APOE) influences cholesterol levels and ischemic heart disease. Although there is no convincing overall association with ischemic stroke, APOE may influence large artery (atherothrombotic) stroke, for which carotid intima-media thickness (CIMT) is an informative intermediate phenotype. We therefore performed a systematic review and meta-analysis of the association between APOE and CIMT. METHODS: We sought all published studies assessing the association between APOE and CIMT. From each study, we extracted available data on study methods, subjects' characteristics, and mean (and standard deviation) CIMT for each genotype or genotype group. We calculated study-specific and random effects pooled differences in mean CIMT between genotype groups, and assessed heterogeneity between studies and predefined subgroups using I(2) and chi(2) statistics. RESULTS: Meta-analysis of 22 published studies (30,879 subjects) showed a significant association between APOE and CIMT (pooled mean difference epsilon 4- versus epsilon 2-allele containing genotypes 46 microm, 95% CI 29 to 62, P<0.00001). We found evidence of small study (mainly publication) bias, with a diminished (but still highly statistically significant) association in studies of >1000 subjects (pooled mean difference 17 microm, 95% CI 12 to 23, P<0.00001). The association was larger among high vascular risk and eastern Asian populations, but this may simply reflect the smaller size of these studies. CONCLUSIONS: Our results show a clear association of APOE with CIMT, even though publication bias means that this is overestimated by the published literature. These findings suggest the possibility of a specific association with large artery ischemic stroke.

Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls.

BACKGROUND AND PURPOSE: Apolipoprotein E genotype (APOE) is associated with cholesterol metabolism, ischemic heart disease, and cerebral amyloid angiopathy, and so may affect risk of both ischemic and hemorrhagic stroke. METHODS: We comprehensively sought and identified studies of the association of apoE with ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). We did meta-analyses to assess the evidence for an association between APOE and the various pathological types and subtypes of stroke, and assessed the effects of several methodological criteria. RESULTS: We analyzed data from 31 eligible studies (26 IS, 8 ICH, and 3 SAH) in 5961 cases and 17 965 controls. epsilon4 allele-containing (epsilon4+) genotypes were significantly associated with IS (odds ratio [OR], 1.11; 95% CI, 1.01 to 1.22) and SAH (OR, 1.42; 95% CI, 1.01 to 1.99) and nonsignificantly with ICH (OR, 1.16; 95% CI, 0.93 to 1.44), whereas epsilon2+ genotypes were associated with ICH (OR, 1.32; 95% CI, 1.01 to 1.74). Associations appeared stronger with epsilon4+ genotypes for large artery compared with other IS subtypes and for Asian compared with white populations, and with epsilon2+ genotypes for lobar compared with deep hemorrhages. However, we found no association between epsilon4+ genotypes and IS when we analyzed only larger studies (>200 cases; OR, 0.99; 95% CI, 0.88 to 1.11) or studies without control selection bias (OR, 0.99; 95% CI, 0.85 to 1.17). CONCLUSIONS: Publication and selection biases make existing studies of APOE and stroke unreliable. Further, very large, methodologically rigorous studies are needed.