Objectives To predict treatment effects for individual patients based on data from randomised trials, taking rosuvastatin treatment in the primary prevention of cardiovascular disease as an example, ...and to evaluate the net benefit of making treatment decisions for individual patients based on a predicted absolute treatment effect.Setting As an example, data were used from the Justification for the Use of Statins in Prevention (JUPITER) trial, a randomised controlled trial evaluating the effect of rosuvastatin 20 mg daily versus placebo on the occurrence of cardiovascular events (myocardial infarction, stroke, arterial revascularisation, admission to hospital for unstable angina, or death from cardiovascular causes).Population 17 802 healthy men and women who had low density lipoprotein cholesterol levels of less than 3.4 mmol/L and high sensitivity C reactive protein levels of 2.0 mg/L or more.Methods Data from the Justification for the Use of Statins in Prevention trial were used to predict rosuvastatin treatment effect for individual patients based on existing risk scores (Framingham and Reynolds) and on a newly developed prediction model. We compared the net benefit of prediction based rosuvastatin treatment (selective treatment of patients whose predicted treatment effect exceeds a decision threshold) with the net benefit of treating either everyone or no one.Results The median predicted 10 year absolute risk reduction for cardiovascular events was 4.4% (interquartile range 2.6-7.0%) based on the Framingham risk score, 4.2% (2.5-7.1%) based on the Reynolds score, and 3.9% (2.5-6.1%) based on the newly developed model (optimal fit model). Prediction based treatment was associated with more net benefit than treating everyone or no one, provided that the decision threshold was between 2% and 7%, and thus that the number willing to treat (NWT) to prevent one cardiovascular event over 10 years was between 15 and 50.Conclusions Data from randomised trials can be used to predict treatment effect in terms of absolute risk reduction for individual patients, based on a newly developed model or, if available, existing risk scores. The value of such prediction of treatment effect for medical decision making is conditional on the NWT to prevent one outcome event.Trial registration number Clinicaltrials.gov NCT00239681.
Sialic acids are negatively charged carbohydrates that cap the glycans of glycoproteins and glycolipids. Sialic acids are involved in various biological processes including cell–cell adhesion and ...immune recognition. In dendritic cells (DCs), the major antigen-presenting cells of the immune system, sialic acids emerge as important regulators of maturation and interaction with other lymphocytes including T cells. Many aspects of how sialic acids regulate DC functions are not well understood and tools and model systems to address these are limited. Here, we have established cultures of murine bone marrow-derived DCs (BMDCs) that lack sialic acid expression using a sialic acid-blocking mimetic Ac
5
3F
ax
Neu5Ac. Ac
5
3F
ax
Neu5Ac treatment potentiated BMDC activation via toll-like receptor (TLR) stimulation without affecting differentiation and viability. Sialic acid blockade further increased the capacity of BMDCs to induce antigen-specific CD8
+
T cell proliferation. Transcriptome-wide gene expression analysis revealed that sialic acid mimetic treatment of BMDCs induces differential expression of genes involved in T cell activation, cell-adhesion, and cell–cell interactions. Subsequent cell clustering assays and single cell avidity measurements demonstrated that BMDCs with reduced sialylation form higher avidity interactions with CD8
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T cells. This increased avidity was detectable in the absence of antigens, but was especially pronounced in antigen-dependent interactions. Together, our data show that sialic acid blockade in BMDCs ameliorates maturation and enhances both cognate T cell receptor–MHC-dependent and independent T cell interactions that allow for more robust CD8
+
T cell responses.
CpG oligonucleotides are short single-stranded synthetic DNA molecules. Upon binding to Toll-like receptor 9 (TLR9), CpG activates immune cells in humans and mice. This results in robust Th1 type ...immunity potentially resulting in clearance of pathogens, reduction of allergy and anti-tumor immunity. However, the effectiveness of CpG as an adjuvant depends on its administration route, with only strong effects seen when CpG is administered locally. As local administration is not always feasible, we generated conjugates to specifically deliver CpG to myeloid cells often abundantly present in tumors. For this we coupled CpG (3′-Thiol-modified phosphorothioate (PTO) CpG-ODN1826 type B (5′-tccatgacgttcctgacgtt-3′)) to monoclonal antibodies (mAbs) directed against the myeloid cell marker CD11b using maleimide-thiol coupling. The CD11b-CpG mAb (αCD11b-CpG) conjugates contained about four CpG molecules/conjugate and displayed binding and internalization characteristics similar to unconjugated CD11b mAbs (αCD11b). The αCD11b-CpG conjugates readily induced maturation of murine dendritic cells (DCs) in a TLR9-dependent manner in vitro. Following intravenous injection, αCD11b-CpG conjugates efficiently targeted CD11b+ immune cells in the blood, lymph nodes and spleen. Finally, injection of αCD11b-CpG conjugates, but not untargeted conjugates, induced maturation of CD11b+ cell subsets in vivo. In conclusion, conjugating CpG to αCD11b enabled specific targeting and activation of myeloid cells in vivo.
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•CpG oligonucleotides can be efficiently coupled to anti-CD11b antibodies.•Anti-CD11b-CpG antibody conjugates are readily internalized by CD11b+ myeloid cells.•Delivery of CpG via antibody-conjugates potently activates myeloid cells via TLR9.•Anti-CD11b-CpG conjugates target and activate CD11b+ myeloid cell subsets in vivo.
Aims To investigate the vascular risk associated with Metabolic Syndrome (MetS) according to different clinical criteria with subsequent vascular events and all-cause mortality in patients with ...coronary artery disease, cerebrovascular disease, peripheral artery disease or abdominal aortic aneurysm and to examine whether patients with MetS at treatment goals for systolic blood pressure (SBP) or low density lipoprotein-cholesterol (LDL-c) level are still at elevated risk. Methods and results Prospective study of 3196 patients with a history or recent diagnosis of clinically manifest vascular disease. During a median follow-up of 3.2 years (interquartile range 1.4–5.4 years), 331 patients died and 373 patients experienced a first vascular event. National Cholesterol Education Program (NCEP) and revised NCEP (NCEP-R)-defined MetS were related to increased risk of vascular events HR – hazard ratio 1.50 (95% CI – confidence interval 1.22–1.84) and 1.50 (1.22–1.87) and all-cause mortality HR 1.49(1.20–1.84) and 1.43 (1.14–1.78). Results were similar in the 2472 patients without type 2 diabetes (DM2) and localization of vascular disease; SBP-category (<140 or ≥140 mmHg) or LDL-category (<2.5 or ≥2.5 mmol/L) did not affect this relation. Conclusion In patients with various manifestations of atherosclerosis, presence of NCEP and NCEP-R-defined MetS is associated with increased risk of cardiovascular events and all-cause mortality, independently of the presence of DM2. This risk is significantly higher than the risk associated with International Diabetes Federation-defined MetS. Also in patients at treatment goals for SBP (<140 mmHg) or LDL-c (<2.5 mmol/L) according to current guidelines, presence of NCEP-R-defined MetS points to a higher vascular risk.
Abstract Background Plasma triglyceride (TG) levels are known to confer an increased risk of vascular disease in healthy populations, but data in high-risk patients are scarce. In this study we ...evaluated the risk on recurrent vascular events conferred by increased plasma TG levels in patients with various clinical manifestations of vascular disease. Methods Prospective cohort study of 5731 patients with clinically manifest vascular disease. Results First new vascular events (myocardial infarction, ischemic stroke, vascular death) occurred in 782 subjects during a median follow-up of 4.9 years (interquartile range 2.5–8.1 years). Patients in the highest plasma TG quintile (> 2.24 mmol/L) had a higher risk for recurrent vascular events (HR 1.45; 95%CI 1.13–1.86) compared with the lowest plasma TG quintile (< 0.97 mmol/L) after adjustments for age, gender, body mass index, smoking, lipid-lowering medication and low-density lipoprotein-cholesterol. The increased risk associated with increasing plasma TG levels was irrespective of the presence of type 2 diabetes (T2DM), but only present in patients without the metabolic syndrome. Furthermore, the increased risk was particularly present in patients with coronary artery disease (CAD) (HR 1.45; 95%CI 1.02–2.08) and was not modified by other lipid levels (p-value for interaction > 0.05). Plasma TG still contributed to vascular risk when other lipid levels were at target level. Conclusions Higher plasma TG levels are associated with increased risk for recurrent vascular events, in particular in CAD patients. This increased risk is independent of the presence of T2DM and the use of lipid-lowering medication and is not modified by other lipid levels.
Abstract Background Resting heart rate (RHR) reflects sympathetic nerve activity and is independently related to the occurrence of cardiovascular events and death in healthy subjects, patients with ...coronary artery disease (CAD) and patients with cardiovascular risk factors. We investigated and compared the risk of RHR on the occurrence of cardiovascular events and death in patients with CAD, cerebrovascular disease (CVD), peripheral arterial disease (PAD) or abdominal aortic aneurysm (AAA). Methods Data were used from a prospective cohort study of 4272 patients with manifest vascular disease: CAD (n = 2244), CVD (n = 930), PAD (n = 823) or AAA (n = 275). RHR was obtained at baseline from an electrocardiogram. The median follow-up time was 4.4 (interquartile range 2.1–7.4) years. The relation between RHR and the occurrence of cardiovascular events and death was estimated by Cox proportional hazard analyses. Results Each increase in RHR of 10 beats/min was related to an increased risk for all-cause mortality (hazard ratio (HR) 1.14; 95% confidence interval (CI) 1.07–1.21) and vascular mortality (HR 1.15; 95% CI 1.06–1.25), but not for myocardial infarction (HR 1.03; 95% CI 0.94–1.14) or ischemic stroke (HR 1.05; 95% CI 0.92–1.20). The relation between an increased RHR and increased risk for all-cause mortality was present irrespective of beta-blocker use and irrespective of the location of vascular disease: CAD (HR 1.23; 95% CI 1.05–1.44), CVD (HR 1.18; 95% CI 1.05–1.33) and PAD/AAA (HR 1.10; 95% CI 1.01–1.20). Conclusions Elevated RHR is associated with increased risk for mortality but not for myocardial infarction or stroke in patients with manifest vascular diseases irrespective of location of vascular disease.
AIMS To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics. ...METHODS AND RESULTS Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50. CONCLUSION Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.
Insulin resistance is accompanied by a cluster of metabolic changes, often referred to as metabolic syndrome. Metabolic syndrome is associated with an increased cardiovascular risk in patients with ...manifest arterial disease. We investigated whether insulin resistance is associated with an increased risk for cardiovascular events in patients with manifest arterial disease without known diabetes and whether this can be explained by the components of the metabolic syndrome or by inflammation.
Prospective cohort study in 2611 patients with manifest arterial disease without known diabetes. Homeostasis model of insulin resistance (HOMA-IR) was used to quantify insulin resistance. The relation of HOMA-IR with cardiovascular events (vascular death, myocardial infarction or stroke) and all cause mortality was assessed with Cox regression analysis. In additional models adjustments were performed for the single components constituting the metabolic syndrome and for inflammation.
HOMA-IR increases with the number of metabolic syndrome components (mean HOMA-IR ± SD in groups with 0, 1, 2, 3, 4 and 5 metabolic syndrome components: 1.4 ± 0.7; 1.8 ± 1.2; 2.4 ± 1.5; 3.1 ± 1.8; 4.0 ± 2.6; and 5.6 ± 3.6 respectively). High HOMA-IR was independently associated with an increased risk of cardiovascular events (tertile 2 vs. 1 HR 1.92; 95%CI 1.20-3.08) (tertile 3 vs.1 HR 1.78; 95%CI 1.10-2.89) and with all cause mortality (tertile 2 vs. 1 HR 1.80; 95%CI 1.04-3.10) (tertile 3 vs.1 HR 1.56; 95%CI 0.88-2.75). These relations were not influenced by the individual components of metabolic syndrome or by inflammation.
In patients with manifest arterial disease without known diabetes, insulin resistance increases with the number of metabolic syndrome components, and elevated insulin resistance increases the risk of new cardiovascular events.
To enable risk stratification of patients with various types of arterial disease by the development and validation of models for prediction of recurrent vascular event risk based on vascular risk ...factors, imaging or both.
Prospective cohort study.
University Medical Centre.
5788 patients referred with various clinical manifestations of arterial disease between January 1996 and February 2010.
788 recurrent vascular events (ie, myocardial infarction, stroke or vascular death) that were observed during 4.7 (IQR 2.3 to 7.7) years' follow-up.
Three Cox proportional hazards models for prediction of 10-year recurrent vascular event risk were developed based on age and sex in addition to clinical parameters (model A), carotid ultrasound findings (model B) or both (model C). Clinical parameters were medical history, current smoking, systolic blood pressure and laboratory biomarkers. In a separate part of the dataset, the concordance statistic of model A was 0.68 (95% CI 0.64 to 0.71), compared to 0.64 (0.61 to 0.68) for model B and 0.68 (0.65 to 0.72) for model C. Goodness-of-fit and calibration of model A were adequate, also in separate subgroups of patients having coronary, cerebrovascular, peripheral artery or aneurysmal disease. Model A predicted < 20% risk in 59% of patients, 20-30% risk in 19% and > 30% risk in 23%.
Patients at high risk for recurrent vascular events can be identified based on readily available clinical characteristics.
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