The Effect and Cost-Effectiveness of Offering a Combined Lifestyle Intervention for the Prevention of Cardiovascular Disease in Primary Care: Results of the Healthy Heart Stepped-Wedge Trial.

OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of offering the combined lifestyle programme "Healthy Heart", addressing overweight, diet, physical activity, smoking and alcohol, to improve lifestyle behaviour and reduce cardiovascular risk. DESIGN: A practice-based non-randomised stepped-wedge cluster trial with two-year follow-up. Outcomes were obtained via questionnaires and routine care data. A cost-utility analysis was performed. During the intervention period, "Healthy Heart" was offered during regular cardiovascular risk management consultations in primary care in The Hague, The Netherlands. The period prior to the intervention period served as the control period. RESULTS: In total, 511 participants (control) and 276 (intervention) with a high cardiovascular risk were included (overall mean ± SD age 65.0 ± 9.6; women: 56%). During the intervention period, 40 persons (15%) participated in the Healthy Heart programme. Adjusted outcomes did not differ between the control and intervention period after 3-6 months and 12-24 months. Intervention versus control (95% CI) 3-6 months: weight: ß -0.5 (-1.08-0.05); SBP ß 0.15 (-2.70-2.99); LDL-cholesterol ß 0.07 (-0.22-0.35); HDL-cholesterol ß -0.03 (-0.10-0.05); physical activity ß 38 (-97-171); diet ß 0.95 (-0.93-2.83); alcohol OR 0.81 (0.44-1.49); quit smoking OR 2.54 (0.45-14.24). Results were similar for 12-24 months. Mean QALYs and mean costs of cardiovascular care were comparable over the full study period (mean difference (95% CI) QALYs: -0.10 (-0.20; 0.002); costs: EUR 106 (-80; 293)). CONCLUSIONS: For both the shorter (3-6 months) and longer term (12-24 months), offering the Healthy Heart programme to high-cardiovascular-risk patients did not improve their lifestyle behaviour nor cardiovascular risk and was not cost-effective on a population level.

Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function.

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Selective prevention of cardiovascular disease using integrated lifestyle intervention in primary care: protocol of the Healthy Heart stepped-wedge trial.

INTRODUCTION: Lifestyle interventions are shown to be effective in improving cardiovascular disease (CVD) risk factors. It has been suggested that general practitioners can play an essential role in CVD prevention. However, studies into lifestyle interventions for primary care patients at high cardiovascular risk are scarce and structural implementation of lifestyle interventions can be challenging. Therefore, this study aims to (1) evaluate (cost-)effectiveness of implementation of an integrated group-based lifestyle programme in primary care practices; (2) identify effective intervention elements and (3) identify implementation determinants of an integrated group-based lifestyle intervention for patients with high cardiovascular risk. METHODS AND ANALYSIS: The Healthy Heart study is a non-randomised cluster stepped-wedge trial. Primary care practices will first offer standard care during a control period of 2-6 months, after which practices will switch (step) to the intervention, offering participants a choice between a group-based lifestyle programme or standard care. Participants enrolled during the control period (standard care) will be compared with participants enrolled during the intervention period (combined standard care and group-based lifestyle intervention). We aim to include 1600 primary care patients with high cardiovascular risk from 55 primary care practices in the area of The Hague, the Netherlands. A mixed-methods process evaluation will be used to simultaneously assess effectiveness and implementation outcomes. The primary outcome measure will be achievement of individual lifestyle goals after 6 months. Secondary outcomes include lifestyle change of five lifestyle components (smoking, alcohol consumption, diet, weight and physical activity) and improvement of quality of life and self-efficacy. Outcomes are assessed using validated questionnaires at baseline and 3, 6, 12 and 24 months of follow-up. Routine care data will be used to compare blood pressure and cholesterol levels. Cost-effectiveness of the lifestyle intervention will be evaluated. Implementation outcomes will be assessed using the RE-AIM model, to assesses five dimensions of implementation at different levels of organisation: reach, efficacy, adoption, implementation and maintenance. Determinants of adoption and implementation will be assessed using focus groups consisting of professionals and patients. ETHICS AND DISSEMINATION: This study is approved by the Ethics Committee of the Leiden University Medical Center (P17.079). Results will be shared with the primary care group, healthcare providers and patients, and will be disseminated through journal publications and conference presentations. TRIAL REGISTRATION NUMBER: NL60795.058.17. Status: pre-results.

Socioeconomic status is not associated with the delivery of care in people with diabetes but does modify HbA1c levels: An observational cohort study (Elzha-cohort 1).

BACKGROUND: Structured primary diabetes care within a collectively supported setting is associated with better monitoring of biomedical and lifestyle-related target indicators amongst people with type 2 diabetes and with better HbA1c levels. Whether socioeconomic status affects the delivery of care in terms of monitoring and its association with HbA1c levels within this approach, is unclear. This study aims to understand whether, within a structured care approach, (1) socioeconomic categories differ concerning diabetes monitoring as recommended; (2) socioeconomic status modifies the association between monitoring as recommended and HbA1c. METHODS: Observational real-life cohort study with primary care registry data from general practitioners within diverse socioeconomic areas, who are supported with the implementation of structured diabetes care. People with type 2 diabetes mellitus were offered quarterly diabetes consultations. "Monitoring as recommended" by professional guidelines implied minimally one annual registration of HbA1c, systolic blood pressure, LDL, BMI, smoking behaviour and physical activity. Regarding socioeconomic status, deprived, advantageous urban and advantageous suburban categories were compared to the intermediate category concerning (a) recommended monitoring; (b) association between recommended monitoring and HbA1c. RESULTS: Aim 1 (n = 13 601 people): Compared to the intermediate socioeconomic category, no significant differences in odds of being monitored as recommended were found in the deprived (OR 0.45 (95% CI 0.19-1.08)), advantageous urban (OR 1.27 (95% CI 0.46-3.54)) and advantageous suburban (OR 2.32 (95% CI 0.88-6.08)) categories. Aim 2 (n = 11 164 people): People with recommended monitoring had significantly lower HbA1c levels than incompletely monitored people (-2.4 (95% CI -2.9; -1.8) mmol/mol). SES modified monitoring-related HbA1c differences, which were significantly higher in the deprived (-3.3 (95% CI -4.3; -2.4) mmol/mol) than the intermediate category (-1.3 (95% CI -2.2; -0.4) mmol/mol). CONCLUSIONS: Within a structured diabetes care setting, socioeconomic status is not associated with recommended monitoring. Socioeconomic differences in the association between recommended monitoring and HbA1c levels advocate further exploration of practice and patient-related factors contributing to appropriate monitoring and for care adjustment to population needs.

Association between GP participation in a primary care group and monitoring of biomedical and lifestyle target indicators in people with type 2 diabetes: a cohort study (ELZHA cohort-1).

OBJECTIVE: Whether care group participation by general practitioners improves delivery of diabetes care is unknown. Using 'monitoring of biomedical and lifestyle target indicators as recommended by professional guidelines' as an operationalisation for quality of care, we explored whether (1) in new practices monitoring as recommended improved a year after initial care group participation (aim 1); (2) new practices and experienced practices differed regarding monitoring (aim 2). DESIGN: Observational, real-life cohort study. SETTING: Primary care registry data from Eerstelijns Zorggroep Haaglanden (ELZHA) care group. PARTICIPANTS: Aim 1: From six new practices (n=538 people with diabetes) that joined care group ELZHA in January 2014, two practices (n=211 people) were excluded because of missing baseline data; four practices (n=182 people) were included. Aim 2: From all six new practices (n=538 people), 295 individuals were included. From 145 experienced practices (n=21 465 people), 13 744 individuals were included. EXPOSURE: Care group participation includes support by staff nurses on protocolised diabetes care implementation and availability of a system providing individual monitoring information. 'Monitoring as recommended' represented minimally one annual registration of each biomedical (HbA1c, systolic blood pressure, low-density lipoprotein) and lifestyle-related target indicator (body mass index, smoking behaviour, physical exercise). PRIMARY OUTCOME MEASURES: Aim 1: In new practices, odds of people being monitored as recommended in 2014 were compared with baseline (2013). Aim 2: Odds of monitoring as recommended in new and experienced practices in 2014 were compared. RESULTS: Aim 1: After 1-year care group participation, odds of being monitored as recommended increased threefold (OR 3.00, 95% CI 1.84 to 4.88, p<0.001). Aim 2: Compared with new practices, no significant differences in the odds of monitoring as recommended were found in experienced practices (OR 1.21, 95% CI 0.18 to 8.37, p=0.844). CONCLUSIONS: We observed a sharp increase concerning biomedical and lifestyle monitoring as recommended after 1-year care group participation, and subsequently no significant difference between new and experienced practices-indicating that providing diabetes care within a collective approach rapidly improves registration of care.

Association between full monitoring of biomedical and lifestyle target indicators and HbA1c level in primary type 2 diabetes care: an observational cohort study (ELZHA-cohort 1).

OBJECTIVE: Management of type 2 diabetes mellitus (T2DM) requires frequent monitoring of patients. Within a collective care group setting, doubts on the clinical effects of registration are a barrier for full adoption of T2DM registration in general practice. We explored whether full monitoring of biomedical and lifestyle-related target indicators within a care group approach is associated with lower HbA1c levels. DESIGN: Observational, real-life cohort study. SETTING: Primary care data registry from the Hadoks (EerstelijnsZorggroepHaaglanden) care group. EXPOSURE: The care group provides general practitioners collectively with organisational support to facilitate structured T2DM primary care. Patients are offered quarterly medical and lifestyle-related consultation. MAIN OUTCOME MEASURE: Full monitoring of each target indicator in patients with T2DM which includes minimally one measure of HbA1c level, systolic blood pressure, LDL, BMI, smoking behaviour and physical exercise between January and December 2014; otherwise, patients were defined as 'incompletely monitored'. HbA1c levels of 8137 fully monitored and 3958 incompletely monitored patients were compared, adjusted for the confounders diabetes duration, age and gender. Since recommended HbA1c values depend on age, medication use and diabetes duration, analyses were stratified into three HbA1c profile groups. Linear multilevel analyses enabled adjustment for general practice. RESULTS: Compared with incompletely monitored patients, fully monitored patients had significantly lower HbA1c levels (95% CI) in the first (-2.03 [-2.53 to -1.52] mmol/mol) (-0.19% [-0.23% to -0.14%]), second (-3.36 [-5.28 to -1.43] mmol/mol) (-0.31% [-0.48% to -0.13%]) and third HbA1c profile group (-1.89 [-3.76 to -0.01] mmol/mol) (-0.17% [-0.34% to 0.00%]). CONCLUSIONS/INTERPRETATION: This study shows that in a care group setting, fully monitored patients had significantly lower HbA1c levels compared with incompletely monitored patients. Since this difference might have considerable clinical impact in terms of T2DM-related risks, this might help general practices in care group settings to overcome barriers on adequate registration and thus improve structured T2DM primary care. From population health management perspective, we recommend a systematic approach to adjust the structured care protocol for incompletely monitored subgroups.

Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium.

Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P < 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86; P < 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09; P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998; P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02; P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11; P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.

Risk factors for bacteremia with uropathogen not cultured from urine in adults with febrile urinary tract infection.

In a prospective study involving 642 patients with febrile urinary tract infection (UTI), we found antimicrobial pretreatment (odds ratio [OR], 3.3), an indwelling urinary catheter (OR, 2.8), and malignancy (OR, 2.7) to be independent risk factors for bacteremia with a uropathogen that was not cultured or recognized in the urine. Although the diagnostic value of blood cultures has been questioned in UTI, we advocate performing blood cultures for patients with these risk factors.