Therapeutic quality control in a regional thrombosis center: the effect of changing the target intensity of anticoagulation with vitamin K antagonists

Background: The target ranges (TR) for anticoagulation with vitamin K antagonists (VKA) in the Netherlands were changed in 2016 from INR 2.0 & ndash;3.5 (& lsquo;low intensity & rsquo;) and INR 2.5 & ndash;4.0 (& lsquo;high intensity & rsquo;) to INR 2.0 & ndash;3.0 and INR 2.5 & ndash;3.5, respectively.Aim: To assess the effect of the TR change on therapeutic quality control (TQC) in a Dutch regional thrombosis center taking care of approximately 3600 & ndash;5500 patients annually.Methods: TQC of chronically treated patients was assessed as the average time in therapeutic range (TTR). Evaluations were performed for non-self-management (NSM), as well as self-management patients. INR percentiles were assessed from all INR determinations in all patients, i.e. including those of induction episodes and patients treated for a short-term.Results: The number of NSM patients treated chronically decreased gradually, while their average age increased, with a marginal but significant gradual increase in bleeding complications. In the period 2011 & ndash;2015, i.e. before the TR change, there was a gradual increase of the TTR in NSM patients from 77.5% to 88.9% (low intensity) and from 75.3% to 84.1% (high intensity). In the same period, the median INR of all patients in the low and high intensity ranges decreased from 2.9 to 2.7, and from 3.3 to 3.2, respectively. The TTR in self-management patients remained virtually constant. After TR changes from 2016 on, the TTR of all NSM patients in the low and high intensity groups decreased to 77% and 70%, respectively, and median INRs decreased to 2.6 and 3.0, respectively.Conclusions: Introduction of internationally harmonized target ranges in 2016 resulted in further lowering of median INR values in both target ranges. As expected, TTR was reduced slightly. These findings, together with a slight increase in average age and concomitant bleeding complications, suggest that the patients on long-term VKA treatment will require intensified monitoring and treatment.Afdeling Klinische Chemie en Laboratoriumgeneeskunde (AKCL

Age at menopause as a risk factor for cardiovascular mortality

Background. Although an association of occurrence of menopause and subsequent oestrogen deficiency with increased cardiovascular disease has been postulated, studies on this association have not shown convincing results. We investigated whether age at menopause is associated with cardiovascular mortality risk. Methods. We

Predictors of cardiac events after major vascular surgery: Role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy

CONTEXT: Patients who undergo major vascular surgery are at increased risk of perioperative cardiac complications. High-risk patients can be identified by clinical factors and noninvasive cardiac testing, such as dobutamine stress echocardiography (DSE); however, such noninvasive imaging techniques carry significant disadvantages. A recent study found that perioperative beta-blocker therapy reduces complication rates in high-risk individuals. OBJECTIVE: To examine the relationship of clinical characteristics, DSE results, beta-blocker therapy, and cardiac events in patients undergoing major vascular surgery. DESIGN AND SETTING: Cohort study conducted in 1996-1999 in the following 8 centers: Erasmus Medical Centre and Sint Clara Ziekenhuis, Rotterdam, Twee Steden Ziekenhuis, Tilburg, Academisch Ziekenhuis Utrecht, Utrecht, and Medisch Centrum Alkmaar, Alkmaar, the Netherlands; Ziekenhuis Middelheim, Antwerp, Belgium; and San Gerardo Hospital, Monza, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy. PATIENTS: A total of 1351 consecutive patients scheduled for major vascular surgery; DSE was performed in 1097 patients (81%), and 360 (27%) received beta-blocker therapy. MAIN OUTCOME MEASURE: Cardiac death or nonfatal myocardial infarction within 30 days after surgery, compared by clinical characteristics, DSE results, and beta-blocker use. RESULTS: Forty-five patients (3.3%) had perioperative cardiac death or nonfatal myocardial infarction. In multivariable analysis, important clinical determinants of adverse outcome were age 70 years or older; current or prior angina pectoris; and prior myocardial infarction, heart failure, or cerebrovascular accident. Eighty-three percent of patients had less than 3 clinical risk factors. Among this subgroup, patients receiving beta-blockers had a lower risk of cardiac complications (0.8% [2/263]) than those not receiving beta-blockers (2.3% [20/855]), and DSE had minimal additional prognostic value. In patients with 3 or more risk factors (17%), DSE provided additional prognostic information, for patients without stress-induced ischemia had much lower risk of events than those with stress-induced ischemia (among those receiving beta-blockers, 2.0% [1/50] vs 10.6% [5/47]). Moreover, patients with limited stress-induced ischemia (1-4 segments) experienced fewer cardiac events (2.8% [1/36]) than those with more extensive ischemia (>/=5 segments, 36% [4/11]). CONCLUSION: The additional predictive value of DSE is limited in clinically low-risk patients receiving beta-blockers. In clinical practice, DSE may be avoided in a large number of patients who can proceed safely for surgery without delay. In clinically intermediate- and high-risk patients receiving beta-blockers, DSE may help identify those in whom surgery can still be performed and those in whom cardiac revascularization should be considered

Urinary sex hormone excretions in premenopausal women and coronary heart disease risk: a nested case-referent study in the DOM-cohort

Contains fulltext : 25164___.PDF (publisher's version ) (Open Access

A high intake of conjugated linoleic acid does not affect liver and kidney function tests in healthy human subjects.

Conjugated linoleic acid (CIA) is consumed widely as a supplement. It Causes hepatomegaly in animals, but toxicological data in humans are limited We therefore studied the effect of a high daily intake of CIA on liver and kidney function in healthy subjects. Twenty Subjects received 14 6 g cis-9,trans-11 CIA and 4.7 g trans-10,cis-12 CIA isomers a day for 3 weeks. Liver and kidney function was measured at 0, 3, 7, 10, 16, and 21 days. Mean values of all tests remained within normal limits Lactate dehydrogenase (mean +/- SD) increased from 290 9 +/- 43.6 to 322.5 +/- 60.7 U/L (p = 0.04) on day 21. One subject exceeded the tipper limit of normal of 450 U/L on day 21. to 472 U/L and another showed an isolated elevation to 555 U/L on day 7. gamma-Glutamyltranspeptidase increased from 12 1 +/- 5 9 to 13 5 +/- 6.2 U/L (p = 0.002) No one exceeded the upper limit of 50 U/L for men and 40 U/L for women A daily intake of 19.3 g CIA for 3 weeks does not produce clinically relevant effects on markers of liver and kidney function in healthy volunteers. (C) 2009 Elsevier Ltd. All rights reserved

Intensive lipid-lowering strategy in patients with diabetes mellitus.

Department of Internal Medicine, Utrecht University Hospital, The Netherlands. AIMS: To assess the feasibility of an intensive lipid-lowering strategy in diabetic subjects pursuing target plasma lipid levels. METHODS: Patients with diabetes mellitus (DM), Type 1 or 2, with plasma lipid levels exceeding target values (LDL-cholesterol 0.9 mmol/l for men and > 1.1 mmol/l for women) were eligible. After 6-12 weeks of diet and glycaemic control, lipid-lowering medication (simvastatin/gemfibrozil/acipimox) was prescribed in steps of incremental dosages and combinations for 30 weeks. RESULTS: Of all eligible clinic patients, 25% initially responded and finally 12% were entered. Thirty-six patients with Type 1 and 59 with Type 2 DM were studied. Mean baseline lipid levels in Type 1 and Type 2 diabetic subjects were: LDL-cholesterol 3.6 and 3.7 mmol/l, triglycerides 1.7 and 2.2 mmol/l, HDL-cholesterol for men 1.1 and 1.0 mmol/l, and for women 1.4 and 1.2 mmol/l, respectively. All three target values were reached in 66% of the patients. LDL-cholesterol was reduced by 1.2 mmol/l in Type 1 and 1.3 mmol/l in Type 2 diabetic patients and triglycerides by 0.7 mmol/l and 1.1 mmol/l, respectively. HDL-cholesterol increased by 0.15 mmol/l and 0.34 mmol/l in men and women with Type 1 diabetes mellitus, respectively. The cholesterol-triglyceride ratio decreased significantly in VLDL in Type 1 diabetes and in IDL in Type 2 diabetes and increased significantly in HDL in Type 2 DM. CONCLUSIONS: A minority of subjects eligible for intensive lipid lowering agreed to participate in a feasibility study, suggesting a potentially large compliance problem for a general lipid-lowering programme in a diabetes clinic. Nevertheless, intensive lipid lowering with drug combinations can attain the recommended target lipid levels in 66% of subjects with diabetes. With this strategy the plasma lipoprotein composition shifts towards a less atherogenic profile. Subjects with diabetes should therefore receive lipid-lowering therapy tailored to reach target levels, rather than standard dosages, in order to reduce atherogenic risk. Publication Types: Clinical Tria

Limitations of the semisynthetic library approach for obtaining human monoclonal autoantibodies to the thyrotropin receptor of Graves' disease.

Department of Immunology, Utrecht University Hospital, Utrecht, The Netherlands. Graves' disease (GD) is characterized by the presence of autoantibodies against the TSH-receptor (TSH-R) which are pathogenic and, upon binding to the receptor, trigger intracellular signal transduction. The autoantibodies are oligoclonal and as they are responsible for disease activity, their characterization would lead to a better understanding of the development of GD. Attempts to isolate anti-TSH-R antibodies from patients have proved to be difficult due to the exceedingly low serum levels due to rarity of these B cells, together with difficulties in obtaining purified TSH-R capable of interacting with patients autoantibodies. We employed phage antibody display technology and performed selection with a previously characterized semisynthetic antibody library on the purified extracellular ectodomain of the TSH-R. We report the isolation of six different anti-TSH-R monoclonal phage antibodies (moPhabs) from this library. All the moPhabs recognized TSH-R and its recombinant fragments by Western blotting, but failed to recognize the native TSH-R by flow cytometry. Consequently, the moPhabs did not lead to TSH-R activation. As these were the first moPhabs to TSH-R, they were analysed in terms of nucleotide and amino acid sequence and epitope specificity on the receptor. The moPhabs used immunoglobulin VH1 and VH3 germ line genes, all associated with Vlambda3 genes. Interestingly, the CDR3 regions of all moPhabs were remarkably similar, though not identical. In light of the common CDR3 usage, the epitopes recognized on TSH-R appeared to be restricted to amino acids residues 405-411 and 357-364. In summary, our results show that semisynthetic libraries may be limited in isolating human monoclonal antibodies that resemble pathogenic antithyrotropin receptor autoantibodies present in patients with GD. It is likely that until preparations of purified TSH-R that can be recognized by patients autoantibodies become available, similar to the recently described glycosylphosphatidylinositol (GPI) anchored TSH-R ectodomain, monoclonal antibodies from phage antibody display to TSH-R will be limited for isolating the rare, pathogenic antibodies of GD

Endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women.

Item does not contain fulltextIn this study, the authors investigated whether combined information on reproductive factors has additive value to the single reproductive factor age at menopause for assessing endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. They conducted a population-based cohort study that included 9,450 postmenopausal women from Nijmegen, the Netherlands, who were aged 35--65 years at enrollment in 1975, with a median follow-up of 20.5 years. A Cox proportional hazards model and Receiver Operating Curves were used to analyze the data. Women aged 52 years or more at menopause had an 18% reduction in cardiovascular mortality (hazard ratio = 0.82, 95% confidence interval (CI): 0.69, 0.98) compared with those aged 44 years or less. Women with more than 18 years of exposure to endogenous estrogen had a statistically significant 20% reduction in cardiovascular mortality (hazard ratio = 0.80, 95 percent CI: 0.67, 0.96) compared with those who had 13 years of exposure or less. The area under the curve of the Receiver Operating Curves for the two models was identical (area under the curve = 0.67, 95 percent CI: 0.66, 0.68). This study shows that age at menopause is related to cardiovascular disease mortality and that a newly developed composite measure of endogenous estrogen exposure does not add to the predictive value of age at menopause for cardiovascular mortality

NO activity in familial combined hyperlipidemia: potential role of cholesterol remnants.

Department of Nephrology and Hypertension, University Hospital Utrecht, The Netherlands. OBJECTIVE: Patients with familial combined hyperlipidemia (FCH) have an increased cardiovascular mortality despite only moderate elevations of LDL-cholesterol. Since endothelial NO release is intimately involved in the anti-atherosclerotic effects of the endothelium, we studied the effect of short-term lipid-lowering therapy on NO-mediated vasodilatation in patients with FCH. In view of only moderate LDL elevations, we evaluated whether alterations in other lipid fractions upon therapy correlated to changes in NO-mediated vasodilatation. METHODS: NO activity was assessed by serotonin-induced, nitric oxide-mediated increase in forearm blood flow (FBF). Measurements were performed 2 weeks off and 4 weeks on lipid-lowering therapy in 12 FCH patients using forearm venous occlusion plethysmography. Control experiments were performed in 12 healthy subjects. RESULTS: Serotonin-induced vasodilatation was impaired in FCH patients (FBF (unit ml/100 ml forearm tissue/min) from 3.0 (0.3) to 4.8 (0.4)) compared to controls (FBF from 2.9 (0.3) to 6.5 (0.6); p < 0.05 vs. FCH). FBF response to serotonin improved significantly upon lipid-lowering therapy (from 3.0 (0.3) to 5.7 (0.5); p < 0.05 treated vs. untreated). The level of improvement in endothelial function was significantly correlated to the absolute reduction of intermediate density lipoproteins upon lipid-lowering therapy (r = -0.64; p < 0.05), whereas it did not correlate to changes in VLDL- or LDL-cholesterol, nor to Lp(a). CONCLUSION: Patients with familial combined hyperlipidemia have impaired NO-mediated vasodilatation, that responds rapidly to lipid lowering medication, and may be related to changes in intermediate density lipoproteins. Publication Types: Clinical Tria