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Van Leeuwen N.,Erasmus Medical Center | Lingsma H.F.,Erasmus Medical Center | De Craen A.J.M.,Leiden University | Nieboer D.,Erasmus Medical Center | And 4 more authors.
Epidemiology | Year: 2016

In epidemiology, the regression discontinuity design has received increasing attention recently and might be an alternative to randomized controlled trials (RCTs) to evaluate treatment effects. In regression discontinuity, treatment is assigned above a certain threshold of an assignment variable for which the treatment effect is adjusted in the analysis. We performed simulations and a validation study in which we used treatment effect estimates from an RCT as the reference for a prospectively performed regression discontinuity study. We estimated the treatment effect using linear regression adjusting for the assignment variable both as linear terms and restricted cubic spline and using local linear regression models. In the first validation study, the estimated treatment effect from a cardiovascular RCT was -4.0 mmHg blood pressure (95% confidence interval: -5.4, -2.6) at 2 years after inclusion. The estimated effect in regression discontinuity was -5.9 mmHg (95% confidence interval: -10.8, -1.0) with restricted cubic spline adjustment. Regression discontinuity showed different, local effects when analyzed with local linear regression. In the second RCT, regression discontinuity treatment effect estimates on total cholesterol level at 3 months after inclusion were similar to RCT estimates, but at least six times less precise. In conclusion, regression discontinuity may provide similar estimates of treatment effects to RCT estimates, but requires the assumption of a global treatment effect over the range of the assignment variable. In addition to a risk of bias due to wrong assumptions, researchers need to weigh better recruitment against the substantial loss in precision when considering a study with regression discontinuity versus RCT design. © 2016 Wolters Kluwer Health, Inc. Source


Birkenhager-Gillesse E.G.,Leiden University | Birkenhager-Gillesse E.G.,Laurens Care Centers | Den Elzen W.P.J.,Leiden University | Achterberg W.P.,Leiden University | And 4 more authors.
Journal of the American Geriatrics Society | Year: 2015

Objectives To examine the association between glycosylated hemoglobin (HbA1c) and incident cardiovascular disease and mortality in 85-year-old individuals without diabetes mellitus from the general population. Design Population-based prospective follow-up study. Setting General population. Participants Individuals without known diabetes mellitus (N = 445, n = 291 female). Measurements HbA1c levels were categorized into three groups (<5.0% (31 mmol/mol), 5.0-5.7% (31-39 mmol/mol; reference), 5.7-6.5% (39-48 mmol/mol)). Results At baseline, a history of myocardial infarction (MI) was more prevalent in subjects in the highest HbA1c group (18%) than in the reference group (7%) (P =.001). Prospectively, those with the highest level of HbA1c at baseline had a risk of incident MI during the 5-year follow-up that was 3.6 (95% confidence interval = 1.5-8.3) times as great as that of the reference group. No association was found between HbA1c level and incident stroke, cardiovascular mortality, or all-cause mortality. Conclusion In individuals aged 85 and older without diabetes mellitus, higher HbA1c is associated with greater risk of MI but not with stroke and mortality. © 2015, The American Geriatrics Society. Source


Poortvliet R.K.E.,Leiden University | Ford I.,University of Glasgow | Lloyd S.M.,University of Glasgow | Sattar N.,University of Glasgow | And 9 more authors.
PLoS ONE | Year: 2012

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70-82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1-1.4; hazard ratio 1.1, 95% confidence interval 1.1-1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2-1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1-1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1-1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1-1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0-1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0-1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0-1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects. © 2012 Poortvliet et al. Source


Poortvliet R.K.E.,Leiden University | De Ruijter W.,Leiden University | De Craen A.J.M.,Leiden University | Mooijaart S.P.,Leiden University | And 5 more authors.
Journal of Hypertension | Year: 2013

Objective: To evaluate the independent contributions of both the trend in SBP and the SBP value at age 90 to the prediction of mortality in nonagenarians. Methods: The trend in SBP between 85 and 90 years and SBP at age 90 years were assessed in a population-based sample of 271 participants (74 men and 197 women) aged 90 years of the Leiden 85-plus Study, an observational population-based prospective follow-up study (started 1997). Primary endpoint, followed up over 5 years (median 3.6 years), was all-cause mortality. Results: A decreasing trend in SBP between 85 and 90 years (decline 2.9 mmHg/year) was associated with increased mortality compared to an average SBP trend (hazard ratio 1.45, 95% confidence interval 1.02-2.06), independent of SBP at age 90. The effect was stronger in institutionalized participants compared to those living independently [hazard ratio 1.87 (1.10-3.19) and hazard ratio 1.30 (0.81-2.09)]. After analysis with a fully adjusted model, the estimate approached unity [hazard ratio 1.08 (0.60-1.86)]. Overall, 90-year-old participants with SBP of 150 mmHg or less had a 1.62 times increased mortality risk compared to those with SBP more than 150 mmHg (1.21-2.20), independent of the SBP trend in preceding years. This applied to those with and without antihypertensive drugs and those with and without history of cardiovascular disease or noncardiovascular disease. In the fully adjusted model, the estimate was 1.47 (0.90-2.40). Conclusion: In very old age, both decreasing trend in SBP over the previous 5 years and the current SBP value independently contribute to prediction of all-cause mortality. Therefore, in individual patients, all available preceding SBP measurements should be taken into account. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Sabayan B.,Leiden University | Wijsman L.W.,Leiden University | Foster-Dingley J.C.,Leiden University | Stott D.J.,University of Glasgow | And 11 more authors.
BMJ (Online) | Year: 2013

Objective To investigate the association between visit-to-visit variability in blood pressure and cognitive function in old age (>70 years). Design Prospective cohort study. Setting PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) study, a collaboration between centres in Ireland, Scotland, and the Netherlands. Participants 5461 participants, mean age 75.3 years, who were at risk of cardiovascular disease. Blood pressure was measured every three months during an average of 3.2 years. Visit-to-visit variability in blood pressure was defined as the standard deviation of blood pressure measurements between visits. Main outcome measures Four domains of cognitive function, testing selective attention, processing speed, and immediate and delayed memory. In a magnetic resonance imaging substudy of 553 participants, structural brain volumes, cerebral microbleeds, infarcts, and white matter hyperintensities were measured. Results Participants with higher visit-to-visit variability in systolic blood pressure had worse performance on all cognitive tests: attention (mean difference high versus low thirds) 3.08 seconds (95% confidence interval 0.85 to 5.31), processing speed ?1.16 digits coded (95% confidence interval ?1.69 to ?0.63), immediate memory ?0.27 pictures remembered (95% confidence interval ?0.41 to ?0.13), and delayed memory ?0.30 pictures remembered (95% confidence interval ?0.49 to ?0.11). Furthermore, higher variability in both systolic and diastolic blood pressure was associated with lower hippocampal volume and cortical infarcts, and higher variability in diastolic blood pressure was associated with cerebral microbleeds (all P<0.05). All associations were adjusted for average blood pressure and cardiovascular risk factors. Conclusion Higher visit-to-visit variability in blood pressure independent of average blood pressure was associated with impaired cognitive function in old age. Source

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