Harold W. de Valk

Comparing Subcutaneous Danaparoid with Intravenous Unfractionated Heparin for the Treatment of Venous Thromboembolism: A Randomized Controlled Trial

Danaparoid (Org 10172; Organon Scientific Development Group, Oss, the Netherlands), a heparinoid with a mean molecular weight of 5500 d, is obtained from the intestinal mucosa of the pig after removal of heparin. It is a mixture of sulfated glycosaminoglycans with low molecular weight: heparan sulfate (84%), dermatan sulfate (12%), and chondroitin sulfate (4%) [1, 2]. Only a subfraction (4%) of heparan sulfate contains the pentasaccharide sequence, common to heparin and to low-molecular-weight heparins, that has a high affinity to antithrombin III. This subfraction acts through the selective inhibition of factor Xa through antithrombin III, which leads to the inhibition of thrombin generation. The fraction of heparan sulfate with a low affinity for antithrombin III does not affect coagulation factors Xa and IIa but contributes substantially to antithrombotic activity, probably through an endothelial cellular mechanism [3]. The dermatan sulfate component of danaparoid activates heparin cofactor II, which acts at the level of factor IIa. The synergistic activity of these three components determines the antithrombotic profile. As reflected in its anti-factor Xa:anti-factor IIa inhibitory ratio of more than 28:1, danaparoid is a more selective inhibitor of factor Xa than heparin or the low-molecular-weight heparins. The dose-related response to danaparoid remains gradual and linear over a wide dosing range, which may contribute to its safety as an antithrombotic drug. Compared with heparin and low-molecular-weight heparins, danaparoid has almost no effect on physiologic platelet function and has low cross-reactivity with heparin-induced antibodies against platelets. The wide therapeutic range of danaparoid and its minimal effect on platelets may render it a safer anticoagulant than heparin or low-molecular-weight heparins. Treatment with unfractionated heparin is limited by the drugs pharmacokinetic, biophysical, and antihemostatic (nonanticoagulant) properties. Heparin must be given in sufficient quantities under frequent monitoring, its dose-response curve is nonlinear and unpredictable in individual persons, and the risk for bleeding increases with increasing doses and duration of treatment. Danaparoid has been shown in animal studies to be more effective than standard heparin or two different low-molecular-weight heparin preparations in preventing the extension of experimentally induced venous thrombi [4]. It has been both safe and effective in the prophylaxis of deep venous thrombosis in patients having cancer surgery [5], hip-fracture surgery [6], or hip-replacement surgery [7] and in patients with nonhemorrhagic stroke [8]. It has been used as an anticoagulant during hemodialysis [9, 10] and in patients with heparin-induced thrombocytopenia [11, 12] or disseminated intravascular coagulation [13]. Data from studies of the treatment of deep venous thrombosis in patients with hemorrhagic stroke indicate that treatment with danaparoid can prevent the extension of venous thromboembolism without aggravating cerebral bleeding [14]. No study has yet assessed the efficacy and safety of danaparoid in the treatment of patients presenting with acute deep venous thrombosis or pulmonary embolism. Danaparoid has a bioavailability of 100% after subcutaneous administration; the bioavailability of unfractionated heparin after subcutaneous injection is only 20% to 30%. Therefore, danaparoid is particularly suitable for subcutaneous administration, much like the low-molecular-weight heparin preparations [15-19], which have a bioavailablity of approximately 90%. Our study was designed to assess the efficacy and safety of two doses of subcutaneously administered danaparoid and of continuous intravenous administration of unfractionated heparin as initial treatment in patients presenting with acute proximal deep venous thrombosis of the leg, pulmonary embolism, or both. Methods Study Design Our study was a randomized, open, parallel-group clinical trial done in one university hospital and two university-affiliated hospitals in the Netherlands. The study protocol and forms giving informed consent were approved by the institutional review board at each hospital. Patients All patients gave witnessed informed consent before being entered into the study. Men and women 18 years of age or older who presented with clinical symptoms of acute proximal deep venous thrombosis of the leg or pulmonary embolism of no more than 7 days duration were eligible. Patients were excluded if they had had intracranial bleeding within 2 months or resuscitation by external chest compression within 48 hours; if they were allergic to heparin; if they were pregnant; if they were receiving treatment with coumarin derivatives; if they had been treated with thrombolytic drugs within 7 days; or if they were receiving ongoing treatment with aspirin, nonsteroidal anti-inflammatory drugs, dextran, or fibrinolytic drugs. The provisional diagnosis of venous thrombosis or pulmonary embolism had to be confirmed within 48 hours after the start of study treatment by compression ultrasonography or contrast venography (whichever could be done soonest) or by ventilation-perfusion lung scan. Treatment was discontinued and the patient was excluded from the study if the clinical diagnosis was not confirmed. Enrollment began in March 1991 and continued through August 1992. Dosing Schedule The efficacy and safety of two dosing schedules of danaparoid were compared with the efficacy and safety of continuous intravenous unfractionated heparin. The schedule for low-dose danaparoid was 1250 anti-factor Xa units given as an intravenous bolus, followed by subcutaneous doses of 1250 anti-factor Xa units every 12 hours. The schedule for high-dose danaparoid was 2000 anti-factor Xa units given as an intravenous bolus, followed by subcutaneous doses of 2000 anti-factor Xa units every 12 hours. The first subcutaneous injection was simultaneous with the intravenous bolus injection. The second subcutaneous injection was given at the time of the first of the routine twice-daily injections, unless this was within 6 hours of the first injection. Unfractionated heparin was given intravenously as a loading dose of 2500 U and was followed by an initial maintenance dose of 30 000 U every 24 hours. This maintenance dose was adjusted to reach activated partial thromboplastin 2.5 to 3.5 times the control values; these times were equivalent to a heparin level of 0.25 to 0.40 U/mL. This was measured daily and 4 hours after any dose adjustment. Study treatment was given for at least 5 days and was continued until an international normalized ratio of at least 3.0 was achieved with oral anticoagulation therapy, which was started 48 hours after the initiation of study treatment. The oral anticoagulant dose was calculated daily using the Thrombotest (Nyegaard and Co., Oslo, Norway; international sensitivity index, 0.94); this was done each morning using plasma samples taken before the morning dose had been given. If the international normalized ratio was below the target level after 8 days of study treatment, the attending physician decided whether to continue heparin therapy, continue danaparoid therapy, or switch patients being treated with danaparoid to intravenous heparin. Study treatment was randomized as follows. Consecutively numbered, identical boxes were kept in each hospital pharmacy; each box contained one of the three treatments, randomized per hospital. After giving informed consent, a patient was treated with medication from the next consecutive box. The investigators were blinded to the randomization schedule. Only when the study medication for one individual patient was delivered did the treatment become known. After being assigned to treatment, patients were excluded from the efficacy analysis only if diagnosis of deep venous thrombosis or pulmonary embolism could not be confirmed within 48 hours of admission. Evaluations and Scheduling The primary method of assessment for recurrence or extension was repeated ultrasonography of the leg, contrast venography, ventilation-perfusion scanning, or both contrast venography and ventilation-perfusion scanning. Assessment was done after at least 5 days and at most 8 days of study treatment, within 24 hours after stopping treatment, or if clinically indicated. Institutional physicians, who were blinded to treatment assignments, interpreted venograms, ultrasonograms, and lung scans. Clinical evidence of recurrence or extension was defined as documented clinical circumstances suggestive of venous thromboembolic disease leading to the discontinuation of study treatment. A daily physical examination (including tests for hemoglobin level, platelet count, and leukocyte count) and a urinalysis to test for erythrocyte count were done. Liver function tests were done and creatinine levels were measured before and at the end of study treatment. Plasma used to measure amidolytic anti-factor Xa activity was collected at the time of screening and at treatment days 2 and 4 (before and 2.5 hours after the morning injection on both days). This plasma was frozen at 20C and stored until assay. Plasma samples were collected at the time of screening for determination of activated partial thromboplastin times before study treatment. Follow-up assessment was done 2 months after the initiation of study treatment to gather information on state of health, recurrence or extension of venous thromboembolism, and bleeding complications. Compression Ultrasonography To establish the extent of thrombosis using ultrasonography [20], the deep venous system was divided into six segments: lower popliteal, upper popliteal, inferior femoral, mid-femoral, upper femoral, and common femoral veins. Each patient was first examined in the supine position so that the superficial femoral, common femoral, and iliac vein segments could be assessed. Patients were then examined in the prone position so

Cognitive Functioning and Brain MRI in Patients with Type 1 and Type 2 Diabetes Mellitus: A Comparative Study

Background/Aims: Diabetes mellitus (DM) may affect the central nervous system, resulting in cognitive impairments. It has been suggested that cognitive impairments are more pronounced in DM2 than in DM1, but studies that directly compare the effects of these 2 types of DM on cognition are lacking. Methods: Forty patients with DM1 (mean duration: 34 years) were compared with 40 age- and education-matched patients who were known to have DM2 (mean duration: 7 years). Extensive neuropsychological assessment focussed on abstract reasoning, memory, attention and executive function, visuoconstruction and information processing speed. Psychological well-being was measured and brain MRIs were obtained. Results:No systematic between-group differences were observed in neuropsychological measures or levels of psychological well-being. DM2 patients showed significantly more deep white matter lesions and cortical atrophy on MRI (p < 0.01). Conclusion: DM1 patients with more than 30 years of DM have a similar cognitive profile and better MRI ratings than age- and education-matched DM2 patients with only 7 years of DM.

Phenylketonuria: High plasma phenylalanine decreases cerebral protein synthesis

Left untreated, phenylketonuria biochemically results in high phenylalanine concentrations in blood and tissues, and clinically especially in severe mental retardation. Treatment consists of severe dietary restriction of phenylalanine with more or less normal intellectual outcome as result when started early enough. It is unclear whether treatment for life is necessary. A clear relationship between plasma phenylalanine concentrations and cerebral outcome exists, but the precise pathophysiological mechanism is not understood. In studies in mice with phenylketonuria, the cerebral protein synthesis rate is decreased when compared to controls. The aim of the present study was to determine the protein synthesis rate in relation to the plasma phenylalanine concentrations in-vivo in patients with phenylketonuria by positron emission tomography brain studies after an intravenous l-[1-(11)C]-tyrosine bolus. Results showed a significant negative relationship (R(2)=0.40, p<0.01) between plasma phenylalanine concentration and the cerebral protein synthesis rate in 19 patients with phenylketonuria. At increased plasma phenylalanine concentrations, i.e. above 600-800micromol/l, the cerebral protein synthesis rate is clearly decreased compared to lower phenylalanine concentrations. These data suggest that cerebral protein metabolism in untreated adults with phenylketonuria can be abnormal due to high plasma phenylalanine concentrations. Hence, we speculate that it is important to continue dietary treatment into adulthood, aiming at plasma phenylalanine concentrations <600-800micromol/l.

Day‐to‐day glucose variability during pregnancy in women with Type 1 diabetes mellitus: glucose profiles measured with the Continuous Glucose Monitoring System

Objective  To observe day‐to‐day variability in glucose levels in pregnant women with Type 1 diabetes using the Continuous Glucose Monitoring System (CGMS) and to assess the usefulness of continuous glucose measurements for adjustment of insulin treatment.

Human Leukocyte Antigen-B27–Associated Uveitis: Long-term Follow-up and Gender Differences

PURPOSE To evaluate clinical features and gender differences in human leukocyte antigen (HLA)-B27-associated acute anterior uveitis (AAU) in long-term follow-up. DESIGN Retrospective cohort study. METHODS The clinical records of 177 HLA-B27-positive patients (96 males [54%] and 81 females [46%]) who sought treatment for acute anterior uveitis (AAU) at the University Medical Center Utrecht between January 1995 and December 2005 were evaluated. All patients had a minimum follow-up of at least one year. The clinical data were analyzed at standardized intervals (one, five, and 10 years after the onset of uveitis). RESULTS Average age at onset of AAU was 36 years, with no differences between males and females. HLA-B27-associated systemic disease developed earlier in males than in females (31 vs 37 years; P=.021). Consequently, at onset of AAU, HLA-B27-associated systemic disease were more frequent in males than in females (25/75 [33%] males vs nine/54 [17%] females; P=.030); however over time, males and females were at equal risk of developing a HLA-B27-associated systemic disease. Bilateral uveitis developed more frequently in females (6/45 [13%] of males vs 11/35, [31%] of females; P=.05). In none of the patients did bilateral visual acuity of less than 0.5 develop after the follow-up of 10 years. CONCLUSIONS The long-term visual prognosis of HLA-B27-associated AAU was favorable, despite the frequent attacks of severe AAU. At the onset of AAU, the prevalence of HLA-B27-associated systemic disease was more frequent in males, but after the onset of uveitis, the risk of developing a HLA-B27-associated systemic disease is similar for both males and females.

Advanced glycation end products, measured as skin autofluorescence and diabetes complications: a systematic review.

BACKGROUND Advanced glycation end products (AGEs) are long-lived tissue proteins that accumulate in diabetes. Skin AGEs measured in biopsy specimens strongly correlated with complications of diabetes. AGEs can also be measured noninvasively by the AGE Reader™ (DiagnOptics B.V., Groningen, The Netherlands). The aim of this review was to systematically review all articles on the association between skin autofluorescence (SAF), measured by the AGE Reader, and complications of diabetes. METHODS We screened PubMed for studies on SAF and complications in diabetes mellitus type 1 and type 2. Seven articles met the inclusion criteria. RESULTS All studies showed positive associations of SAF with one or more complications (all-cause mortality, cardiovascular mortality, micro- and macrovascular complications, neuropathy, and nephropathy), except retinopathy. Only three studies were of prospective design, with a follow-up of 3-5 years; the other four studies were cross-sectional. Studies were of large clinical heterogeneity. CONCLUSIONS This systematic review of literature showed an association of SAF with end-organ complications in diabetes, except retinopathy, in all seven studies. However, studies were of large clinical heterogeneity, only three studies had a prospective design, and five studies were from the same research group. More prospective studies, with a longer period of follow-up, larger group size, and strict definitions of complications and end points, are needed to demonstrate the potential role and benefit in clinical management before the widespread use of the AGE Reader can be recommended.

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

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.

Insulin during pregnancy, labour and delivery.

Optimal glycaemic control is of the utmost importance to achieve the best possible outcome of a pregnancy complicated by diabetes. This holds for pregnancies in women with preconceptional type 1 or type 2 diabetes as well as for pregnancies complicated by gestational diabetes. Glycaemic control is conventionally expressed in the HbA1c value but the HbA1c value does not completely capture the complexity of glycaemic control. The daily glucose profile measured by the patients themselves through measurements performed in capillary blood obtained by finger stick provides valuable information needed to adjust insulin therapy. Hypoglycaemia is the major threat to the pregnant woman or the woman with tight glycaemic control in the run-up to pregnancy. Repetitive hypoglycaemia can lead to hypoglycaemia unawareness, which is reversible with prevention of hypoglycaemia. A delicate balance should be struck between preventing hyperglycaemia and hypoglycaemia. Insulin requirements are not uniform across the day: it is low during the night with a more or less pronounced rise at dawn, followed by a gradual decrease during the remainder of the day. A basal amount of insulin is needed to regulate the endogenous glucose production, short-acting insulin shots are needed to handle exogenous glucose loads. Insulin therapy means two choices: the type of insulin used and the method of insulin administration. Regarding the type of insulin, the choice is between human and analogue insulins. The analogue short-acting insulin aspart has been shown to be safe during pregnancy in a randomised trial and has received registration for this indication; the short-acting analogue insulin lispro has been shown to be safe in observational studies. No such information is available on the long-acting insulin analogues detemir and glargine and both are prescribed off-label with human long-acting insulin as obvious alternatives. Randomised trials have not been able to show superiority of continuous subcutaneous insulin administration (CSII (insulin pump)) over intensive insulin injection therapy (multiple-dose insulin (MDI)) on any maternal or foeto-neonatal end point. However, group sizes were far too small to allow assessment of superiority and issues such as manageability of the disease and quality of life were never assessed. These two issues are of major importance to patients. The first trimester is often the period of most hypoglycaemic events, and insulin therapy should be especially closely monitored and adjusted in this period. After midterm, insulin requirements increase. Continuous glucose monitoring can offer better insights into the glycaemic profile than self-monitoring of blood glucose levels by the patients but the place of these new monitoring techniques has yet to be established more clearly. Insulin therapy during labour means short-acting insulin adjusted to achieve glucose levels between 4 and 8 mmol l(-1) to prevent neonatal hypoglycaemia as much as possible. After delivery, glycaemic control must be relaxed to prevent hypoglycaemia, especially in women who breastfeed.

Risk factors for childhood overweight in offspring of type 1 diabetic women with adequate glycemic control during pregnancy: nationwide follow-up study in the Netherlands.

OBJECTIVE Pregnancy in type 1 diabetic women remains a high-risk situation for both mother and child. In this study, we investigated long-term effects on body composition, prevalence of overweight, and insulin resistance in children of type 1 diabetic women who had had adequate glycemic control during pregnancy (mean A1C 6.2%), and we related their outcome to perinatal factors, including macrosomia (birth weight >90th percentile). RESEARCH DESIGN AND METHODS Anthropometric measurements were performed at 6–8 years of age in 213 offspring of type 1 diabetic mothers who participated in a previous nationwide study. Homeostasis model assessment of insulin resistance (HOMA-IR) was determined from a fasting blood sample in 155 of these children. In addition, we studied BMI standard deviation score (SDS) growth trajectories. Results were compared with national reference data. RESULTS The prevalence of overweight in the study population was not different from that in the reference population. However, children who were born macrosomic showed twice as much overweight as nonmacrosomic children. Macrosomia and maternal overweight were independent predictors of childhood overweight. Overweight children showed an increase in BMI SDS starting already after 6 months of age and had a significantly increased HOMA-IR. CONCLUSIONS In type 1 diabetic women with adequate glycemic control during pregnancy, long-term effects on body composition and overweight in their offspring at school age are limited and related mainly to macrosomia at birth. Possible targets for prevention of childhood overweight are fetal macrosomia, maternal overweight, and an increase in BMI SDS during the first years of life.

Glycemic variability in inadequately controlled type 1 diabetes and type 2 diabetes on intensive insulin therapy: a cross-sectional, observational study.

BACKGROUND Glycemic variability is suggested to be a predictor for the risk of complications of diabetes. A multitude of parameters to express glycemic variability have been described, but no gold standard exists. The easy measurable parameter SD has been shown to be strongly related to other parameters in a group of patients with mostly well-controlled type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). Glycemic variability is higher in T1DM compared with T2DM in mixed populations with different treatments, but studies in patients on intensive insulin treatment are lacking. Therefore in this study we investigate different parameters of glycemic variability and differences between T1DM and T2DM in inadequately controlled patients on intensive insulin treatment. METHODS In this cross-sectional, observational study we describe glycemic variability, measured as SD, coefficient of variation, continuous overall net glycemic action, and mean of daily differences in a cohort of inadequately controlled T1DM (n = 166) and T2DM (n = 58) patients on intensive insulin treatment. RESULTS SD of 48 h (SD(total)) was highly correlated to all other measured parameters of glycemic variability (r = 0.66-0.88). All parameters of glycemic variability were significantly higher in T1DM compared to T2DM (P < 0.001), although hemoglobin A1c and mean glucose were comparable and treatment regimen was the same. In the cohort of T2DM patients but not T1DM, a longer duration of insulin therapy was associated with higher glycemic variability. CONCLUSIONS SD(total) is a conveniently measurable parameter to express glycemic variability in patients with inadequate control with intensive insulin therapy. Patients with T1DM and long-lasting T2DM have the highest glycemic variability.