Barbara A. Hutten

Incidence of Recurrent Thromboembolic and Bleeding Complications Among Patients With Venous Thromboembolism in Relation to Both Malignancy and Achieved International Normalized Ratio: A Retrospective Analysis

PURPOSE Initial heparinization followed by vitamin K antagonists is the treatment of choice for patients with venous thromboembolism. There is controversy whether known malignancy is a risk factor for recurrences and bleeding complications during this treatment. Furthermore, the incidence of such events in these patients is dependent on the achieved International Normalized Ratio (INR). The aim of this study was to assess the incidence of venous thromboembolic recurrence and major bleeding among patients with venous thromboembolism in relation to both malignancy and the achieved INR. PATIENTS AND METHODS In a retrospective analysis, the INR-specific incidence of venous thromboembolic and major bleeding events during oral anticoagulant therapy was calculated separately for patients with and without malignancy. Eligible patients participated in two multicenter, randomized clinical trials on the initial treatment of venous thromboembolism. Patients were initially treated with heparin (standard or low-molecular weight). Treatment with vitamin K antagonists was started within 1 day and continued for 3 months, with a target INR of 2.0 to 3.0. RESULTS In 1,303 eligible patients (264 with malignancy), 35 recurrences and 12 bleeds occurred. Patients with malignancy, compared with nonmalignant patients, had a clinically and statistically significantly increased overall incidence of recurrence (27.1 v 9.0, respectively, per 100 patient-years) as well as bleeding (13.3 v 2.1, respectively, per 100 patient-years). In both groups of patients, the incidence of recurrence was lower when the INR was above 2.0 compared with below 2.0. CONCLUSION Although adequately dosed vitamin K antagonists are effective in patients with malignant disease, the incidence of thrombotic and bleeding complications remains higher than in patients without malignancy.

Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage

BACKGROUND Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs. METHODS In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events. RESULTS Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, -2.6 percentage points; 95% confidence interval [CI], -15.0 to 9.9; aspirin only vs. placebo, -6.2 percentage points; 95% CI, -18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, -10.8 to 15.0; aspirin alone vs. placebo -5.4 percentage points; 95% CI, -18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups. CONCLUSIONS Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. (Current Controlled Trials number, ISRCTN58496168.)

Oral anticoagulation self-management and management by a specialist anticoagulation clinic: a randomised cross-over comparison

BACKGROUND Vitamin K antagonist treatment is effective for prevention and treatment of thromboembolic events but frequent laboratory control and dose-adjustment are essential. Small portable devices have enabled patient self-monitoring of anticoagulation and self-adjustment of the dose. We compared this self-management of oral anticoagulant therapy with conventional management by a specialist anticoagulation clinic in a randomised cross-over study. METHODS 50 patients on long-term oral anticoagulant treatment were included in a randomised controlled crossover study. Patients were self-managed or were managed by the anticoagulation clinic for a period of 3 months. After this period the alternative strategy was followed for each patient. Prothrombin time (expressed as international normalised ratio [INR]) were measured at intervals of 1-2 weeks in both periods without knowledge of type of management. The primary endpoint was the number of measurements within the therapeutic range (therapeutic target value +/-50.5 INR units). FINDINGS There was no significant difference in the overall quality of control of anticoagulation between the two study periods. Patients were for 55% and for 49% of the treatment period within a range of +/-0.5 from the therapeutic target INR during self-management and anticoagulation clinic management, respectively (p=0.06). The proportion of patients who spent most time in the therapeutic target range was larger during self-management than during anticoagulation clinic-guided management. The odds ratio for a better control of anticoagulation (defined as the period of time in the therapeutic target range) during self-management compared with anticoagulation clinic-guided management was 4.6 (95% CI 2.1-10.2). A patient-satisfaction assessment showed superiority of self-management over conventional care. INTERPRETATION Self-management of INR in the population in this study is feasible and appears to result in control of anticoagulation that is at least equivalent to management by a specialist anticoagulation clinic. It is also better appreciated by patients. Larger studies are required to assess the effect of this novel management strategy on the incidence of thromboembolic or bleeding complications.

Sympathetic Activation Markedly Reduces Endothelium-Dependent, Flow-Mediated Vasodilation

OBJECTIVES We sought to evaluate whether increased sympathetic outflow may interfere with flow-mediated dilation (FMD). BACKGROUND Endothelial function, assessed as FMD, is frequently used as an intermediate end point in intervention studies. Many disease states with increased sympathetic tone are also characterized by endothelial dysfunction. METHODS Sixteen healthy volunteers underwent FMD studies with and without concomitant sympathetic stimulation. Intra-arterial nitroglycerin (NTG) infusion was used to assess endothelium-independent vasodilation. Pathophysiologically relevant sympathetic stimulation was achieved by baroreceptor unloading, using a lower body negative pressure box. In a subset of eight volunteers, this protocol was repeated during loco-regional alpha-adrenergic blockade by intra-arterial infusion of phentolamine (PE). Reactive hyperemic flow was assessed with strain-gauge phlethysmography. RESULTS Overall, FMD responses (8.3 +/- 3.4%) were significantly attenuated by concomitant sympathetic stimulation (3.6 +/- 3.4%, p < 0.01). Loco-regional alpha-adrenergic blockade had no effect on baseline FMD responses (10.7 +/- 4.7%), whereas the attenuation by sympathetic stimulation was abolished completely during PE co-infusion (11.5 +/- 3.3%). During intra-arterial NTG infusions, arterial diameters relative to baseline were not significantly different between the four possible stages. CONCLUSIONS Sympathetic stimulation, at a clinically relevant range, significantly impairs the FMD response by an alpha-adrenergic mechanism.

Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia.

Patients with familial hypercholesterolaemia have severe coronary-artery disease early in adult life. Whether lipid-lowering treatment should be started in childhood remains to be established. We therefore assessed 201 children heterozygous for familial hypercholesterolaemia and 80 unaffected siblings (both age ranges 8-18 years) with B-mode ultrasound to measure carotid wall intima-media thickness. Mean combined carotid intima-media thickness of heterozygotes was significantly greater than that of unaffected siblings (0.494 mm [SD 0.051] vs 0.472 [SD 0.049], p=0.002). A significant deviation in intima-media thickness was noted from age 12 years in children with familial hypercholesterolaemia. Findings on multivariate analysis showed LDL cholesterol, age, and sex to be strong and independent predictors of intima-media thickness. Since raised LDL cholesterol concentrations can be lowered efficiently, clinical studies are needed to investigate long-term safety and effectiveness of statin treatment in children with familial hypercholesterolaemia.

Statin treatment in children with familial hypercholesterolemia - The younger, the better

Background— We previously demonstrated in a randomized placebo-controlled trial that 2-year pravastatin treatment induced a significant regression of carotid intima-media thickness (IMT) in 8- to 18-year-old children with familial hypercholesterolemia. Subsequently, we continued to follow up these children to explore the relation between the age of statin initiation and carotid IMT after follow-up on statin treatment. We also examined safety aspects of statin therapy during this long-term follow-up. Methods and Results— All 214 children who initially participated in the previous placebo-controlled study were eligible for the follow-up study. After completion of the placebo-controlled study, all children continued treatment with pravastatin 20 or 40 mg, depending on their age. Blood samples were taken on a regular basis for lipids and safety parameters, and a carotid IMT measurement was performed after an average treatment period of 4.5 years. Follow-up data for 186 children were available for the statistical analyses. Multivariate analyses revealed that age at statin initiation was an independent predictor for carotid IMT after follow-up with adjustment for carotid IMT at initiation of statin treatment, sex, and duration of treatment. Early initiation of statin treatment was associated with a subsequently smaller IMT. Furthermore, no serious laboratory adverse events were reported during follow-up, and statin treatment had no untoward effects on sexual maturation. Conclusions— These data indicate that early initiation of statin treatment delays the progression of carotid IMT in adolescents and young adults. The present study shows for the first time that early initiation of statin therapy in children with familial hypercholesterolemia might be beneficial in the prevention of atherosclerosis in adolescence.

Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome.

Summary.  Background: About 30% of patients with an episode of adequately treated deep venous thrombosis (DVT) develop the postthrombotic syndrome (PTS) within 2 years. During treatment with vitamin K antagonists (VKA) patients spend only 60% of time between an International Normalized Ratio (INR) of 2.0 and 3.0. We hypothesized that patients who spend a large amount of their time beneath this range will have an increased risk of the PTS. Objective: To investigate the relation between the quality of anticoagulant therapy with VKA and the risk of the development of the PTS. Methods: The time spent beneath the therapeutic range was calculated for patients with a first episode of DVT, who were treated with VKA for at least 3 months. At follow‐up assessments for a maximum of 5 years, presence and severity of signs and symptoms of PTS were recorded. Results: A total of 244 patients, with a median duration of follow‐up of 4.9 years were included for analysis. Of these, 81 patients (33%) developed the PTS. The multivariate model showed that patients who spend more than 50% of their time beneath an INR level of 2.0 are at higher risk for PTS [odds ratio (OR): 2.71, 95% CI: 1.44–5.10]. Conclusions: Low quality treatment with VKA, which is a common condition, is related to the occurrence of the PTS in patients with DVT. Strategies aimed at improving the quality of long‐term anticoagulation might have the potential to reduce the incidence of this complication.

A Systematic Review and Meta-Analysis of Statin Therapy in Children With Familial Hypercholesterolemia

Objective—Functional and morphological changes of the arterial wall already present in young children with heterozygous familial hypercholesterolemia (HeFH) suggest that treatment should be initiated early in life to prevent premature atherosclerotic cardiovascular disease. The purpose of this study was to assess the efficacy and particularly safety of statin therapy in children with HeFH. Methods and Results—We performed a meta-analysis of randomized, double-blind, placebo-controlled trials evaluating statin therapy in children aged 8 to 18 years with HeFH. Six studies (n=798 children) with 12 to 104 weeks of treatment were included. Total cholesterol, LDL cholesterol, and apolipoprotein B were significantly reduced, whereas HDL cholesterol and apolipoprotein A1 were significantly increased by statin therapy. No statistically significant differences were found between statin- and placebo-treated children with respect to the occurrence of adverse events (RR 0.99; 95% CI: 0.79 to 1.25), sexual development (RR of advancing ≥1 stage in Tanner classification 0.96; 95% CI: 0.79 to 1.17), muscle toxicity (RR of CK ≥10 times the upper limit of normal [ULN] 1.38; 95% CI: 0.18 to 10.82), or liver toxicity (RR of ≥3 times the ULN for ASAT 0.98; 95% CI: 0.23 to 4.26 and for ALAT 2.03; 95% CI: 0.24 to 16.95). We found a minimal difference in growth in favor of the statin group (0.33 cm; 95% CI: 0.03 cm to 0.63 cm). Conclusion—In addition to the fact that statin treatment is efficacious, our results support the notion that statin treatment in children with HeFH is safe. Thus, even though further studies are required to assess lifelong safety, statin treatment should be considered for all children aged 8 to 18 with HeFH.

Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.

IMPORTANCE Familial hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes. OBJECTIVE To assess the association between type 2 diabetes prevalence and familial hypercholesterolemia. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study in all individuals (n = 63,320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014. EXPOSURES Deleteriousness and nondeleteriousness of familial hypercholesterolemia mutations were based on literature or laboratory function testing. Low-density lipoprotein (LDL) receptor mutations were considered more severe than apolipoprotein B gene (APOB) mutations, and receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations. MAIN OUTCOMES AND MEASURES Prevalence of type 2 diabetes. RESULTS The prevalence of type 2 diabetes was 1.75% in familial hypercholesterolemia patients (n = 440/25,137) vs 2.93% in unaffected relatives (n = 1119/38,183) (P < .001; odds ratio [OR], 0.62 [95% CI, 0.55-0.69]). The adjusted prevalence of type 2 diabetes in familial hypercholesterolemia, determined using multivariable regression models, was 1.44% (difference, 1.49% [95% CI, 1.24%-1.71%]) (OR, 0.49 [95% CI, 0.41-0.58]; P < .001). The adjusted prevalence of type 2 diabetes by APOB vs LDL receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.48-0.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence for receptor-deficient vs receptor-negative mutation carriers was 1.44% vs 1.12% (OR, 0.49 [95% CI, 0.40-0.60] vs OR, 0.38 [95% CI, 0.29-0.49]), respectively (P for trend <.001 in both comparisons). CONCLUSIONS AND RELEVANCE In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes.

Compromised LCAT Function Is Associated With Increased Atherosclerosis

Background—Prospective epidemiological studies have shown that low plasma levels of HDL cholesterol (HDL-C) are associated with an increased risk for cardiovascular disease (CVD). Despite nearly 40 years of research, however, it is unclear whether this also holds true for individuals with severely reduced levels of HDL-C due to mutations in the lecithin:cholesterol acyltransferase (LCAT) gene. Better insight into CVD risk in these individuals may provide clues toward the potential of LCAT as a pharmaceutical target to raise HDL-C levels. Methods and Results—Lipids, lipoproteins, high-sensitivity C-reactive protein (CRP), and carotid artery intima-media thickness (IMT) were assessed in 47 heterozygotes for LCAT gene mutations and 58 family controls. Compared with controls, heterozygotes presented with a mean 36% decrease in HDL-C levels (P<0.0001), a 23% increase in triglyceride levels (P<0.0001), and a 2.1-fold increase in CRP levels (P<0.0001). Mean carotid IMT was significantly increased in heterozygotes compared with family controls (0.623±0.13 versus 0.591±0.08 mm). After adjustment for age, gender, and alcohol use, this difference proved statistically significant (P<0.0015). Conclusions—The data show that heterozygosity for LCAT gene defects is associated with low HDL-C levels and elevated concentration of triglycerides and CRP in plasma. This phenotype underlies increased IMT in carriers versus controls, which suggests that LCAT protects against atherosclerosis. This in turn indicates that targeting LCAT to raise HDL-C may reduce CVD risk.