Geloof in kloppend bewijs

Rede, In verkorte vorm uitgesproken ter gelegenheid van het aanvaarden van het ambt van bijzonder hoogleraar Klinische epidemiologie van hart- en vaatziekten aan het Erasmus MC, faculteit van de Erasmus Universiteit Rotterdam op 20 maart 2009. De leidende gedachte binnen het vakgebied Klinische epidemiologie is dat medisch handelen gebaseerd dient te zijn op het best beschikbare bewijs van zijn werkzaamheid en doeltreffendheid. Dat bewijs is niet gegrond op de persoonlijke ervaring van patiënten, noch op de klinische expertise van individuele artsen, hoe waardevol deze elementen ook zijn. Maar het bewijs voor de effectiviteit van het klinisch handelen is bij voorkeur afkomstig van wetenschappelijk onderzoek onder groepen patiënten, waarin theoretische concepten worden getoetst, en waarbij gezocht wordt naar relaties tussen het optreden en het beloop van ziekten enerzijds, en verklarende factoren of determinanten daarvan anderzijds.|1 Deze determinanten kunnen zowel oorzakelijke als niet-oorzakelijke factoren zijn. Vanzelfsprekend dient onderzoek naar determinant-uitkomst relaties te worden opgezet en uitgevoerd in overeenstemming met kwalitatief hoogstaande standaarden

Case study: Ticagrelor in plato and prasugrel in triton-timi 38 and trilogy-acs trials in patients with acute coronary syndromes

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Tailored reperfusion therapy of patients with evolving myocardial infarction: Models to guide clinical decision making

Myocardial infarction is one of the leading causes of death among adults in the Western World. In The Netherlands, yearly approximately 20,000 men and 10,000 women are admitted with this diseas

Platelet Glycoprotein IIb/IIIa Receptor Inhibition in Non-ST-Elevation Acute Coronary Syndromes

BACKGROUND: Glycoprotein (GP) IIb/IIIa receptor blockers prevent life-threatening cardiac complications in patients with acute coronary syndromes without ST-segment elevation and protect against thrombotic complications associated with percutaneous coronary interventions (PCIs). The question arises as to whether these 2 beneficial effects are independent and additive. METHODS AND RESULTS: We analyzed data from the CAPTURE, PURSUIT, and PRISM-PLUS randomized trials, which studied the effects of the GP IIb/IIIa inhibitors abciximab, eptifibatide, and tirofiban, respectively, in acute coronary syndrome patients without persistent ST-segment elevation, with a period of study drug infusion before a possible PCI. During the period of pharmacological treatment, each trial demonstrated a significant reduction in the rate of death or nonfatal myocardial infarction in patients randomized to the GP IIb/IIIa inhibitor compared with placebo. The 3 trials combined showed a 2.5% event rate in this period in the GP IIb/IIIa inhibitor group (N=6125) versus 3.8% in placebo (N=6171), which implies a 34% relative reduction (P<0.001). During study medication, a PCI was performed in 1358 patients assigned GP IIb/IIIa inhibition and 1396 placebo patients. The event rate during the first 48 hours after PCI was also significantly lower in the GP IIb/IIIa inhibitor group (4. 9% versus 8.0%; 41% reduction; P<0.001). No further benefit or rebound effect was observed beyond 48 hours after the PCI. CONCLUSIONS: There is conclusive evidence of an early benefit of GP IIb/IIIa inhibitors during medical treatment in patients with acute coronary syndromes without persistent ST-segment elevation. In addition, in patients subsequently undergoing PCI, GP IIb/IIIa inhibition protects against myocardial damage associated with the intervention

Joint models with multiple longitudinal outcomes and a time-to-event outcome: a corrected two-stage approach

Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a novel approach that enables the fitting of such models with more realistic computational times. The idea behind the approach is to split the estimation of the joint model in two steps: estimating a multivariate mixed model for the longitudinal outcomes and then using the output from this model to fit the survival submodel. So-called two-stage approaches have previously been proposed and shown to be biased. Our approach differs from the standard version, in that we additionally propose the application of a correction factor, adjusting the estimates obtained such that they more closely resemble those we would expect to find with the multivariate joint model. This correction is based on importance sampling ideas. Simulation studies show that this corrected two-stage approach works satisfactorily, eliminating the bias while maintaining substantial improvement in computational time, even in more difficult settings

Joint models for longitudinal and time-to-event data in a case-cohort design

Studies with longitudinal measurements are common in clinical research. Particular interest lies in studies where the repeated measurements are used to predict a time‐to‐event outcome, such as mortality, in a dynamic manner. If event rates in a study are low, however, and most information is to be expected from the patients experiencing the study endpoint, it may be more cost efficient to only use a subset of the data. One way of achieving this is by applying a case‐cohort design, which selects all cases and only a random samples of the noncases. In the standard way of analyzing data in a case‐cohort design, the noncases who were not selected are completely excluded from analysis; however, the overrepresentation of the cases will lead to bias. We propose to include survival information

Prognostic Significance of Angiogenic Growth Factor Serum Levels in Patients With Acute Coronary Syndromes

BACKGROUND: In patients with acute coronary syndromes, compensatory processes are initiated, including angiogenesis and endothelial regeneration of ruptured or eroded plaques. Angiogenic growth factors like vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and basic fibroblast growth factor (bFGF) are upregulated during ischemia. However, it is unknown whether their serum levels are related to clinical outcome. METHODS AND RESULTS: We measured VEGF, HGF, and bFGF levels in 1090 patients with acute coronary syndromes. Angiographic evaluation was performed at baseline as well as death, and nonfatal myocardial infarctions were recorded during 6-month follow-up. HGF and VEGF, but not bFGF, were significantly and independently associated with the patients' outcome. Patients with elevated VEGF serum levels suffered from adverse outcome (adjusted hazard ratio, 2.50 [1.52 to 4.82]; P=0.002). VEGF elevation was associated with evidence of ischemia and was a significant predictor of the effect of glycoprotein IIb/IIIa inhibition. In contrast, patients with high HGF levels had a significantly lower event rate compared with patients with low HGF levels (adjusted hazard ratio, 0.33 [0.21 to 0.51]; P<0.001). HGF levels did not correlate with evidence of ischemia and did not predict the effect of abciximab. Intriguingly, however, HGF levels significantly correlated with angiographically visible collateralization of the target vessel (22.4% versus 10.5%; P<0.001). CONCLUSIONS: The angiogenic growth factors VEGF and HGF are independent predictors of the patients' prognosis in acute coronary syndromes. Whereas VEGF elevation correlated with the evidence of myocardial ischemia and indicated an adverse outcome, HGF elevation was independent of ischemia and associated with improved collateralization as well as a favorable prognosis

Overweight and Class I Obesity Are Associated with Lower 10-Year Risk of Mortality in Brazilian Older Adults: The Bambuí Cohort Study of Ageing

Background: Prospective studies mostly with European and North-American populations have shown inconsistent results r