Desiderius P. M. Brandjes

Reasons for undertreatment with oral anticoagulants in frail geriatric outpatients with atrial fibrillation: a prospective, descriptive study.

ObjectivesThe main aims of the study were to explore whether oral anti-coagulation (OAC) for atrial fibrillation (AF) in geriatric outpatients is prescribed in accordance with international (American College of Cardiology/American Heart Association/European Society of Cardiology [ACC/AHA/ESC]) and Dutch national guidelines for the general practitioner (GP) and to identify whether age and selected co-morbid conditions are associated with undertreatment. As a secondary objective, we wanted to establish how many patients discontinue OAC because of major bleeding.MethodsIn 2004, at the first visit of all patients to the geriatric day clinic of the Slotervaart Hospital in Amsterdam, the Netherlands, demographic data, Mini-Mental State Examination score, medical history, Charlson Comorbidity Index score, and data on medication use and changes were documented. The presence of AF was established by assessment of medical history information obtained by the GP, the history taken from patients and their caregivers, and the results of clinical evaluation, including ECG findings. Associations between the use of OAC, demographic data and co-morbid conditions registered in the Dutch NHG (Nederlands Huisartsen Genootschap [Dutch College of General Practitioners]) standard for GPs as risk factors for stroke or contraindications to the use of OAC were analysed. The reasons for discontinuing OAC were assessed after 4 years by requesting the information from the anticoagulation services or the GP.ResultsAt the time of the initial visit, 17.5% of the 807 outpatients had chronic AF (n= 135) or were known to have paroxysmal AF (n = 6). The mean age of the 141 patients in this cohort was 84.3 years (SD 6.2 years). Co-morbid conditions increasing the risk of stroke were present in 129 patients (91.5%). Contraindications to the use of OAC were observed in 118 patients (83.7%). Of the 116 patients with AF in their history before their visit, 57.8% were being treated with OAC at the time of their visit. After comprehensive geriatric assessment, 73 (51.8%) of the 141 patients with chronic or paroxysmal AF were continued on OAC. Of the 141 patients with chronic or paroxysmal AF, 110 (78.0%) had both extra stroke risk factors and contraindications to the use of OAC. Only increasing age was significantly and independently associated with not being prescribed anticoagulants (p<0.001). At the 4-year follow-up, OAC had been discontinued in 5.5% of patients because of major bleeding; three patients (4.1%) taking OAC had died as a result of major bleeding, and one other patient had discontinued treatment because of a major, non-lethal bleeding episode.ConclusionApplying the NHG standard for appropriate prescription, and disregarding age as a risk factor or contraindication, in this population, 14 of 141 patients (9.9%) were inappropriately prescribed OAC, salicylates or no prophylaxis. Since only patient age was associated with not prescribing OAC in this study, higher age still seems to be considered the most important contraindication to anticoagulation therapy. Implementation of better models for stratifying bleeding risk in the frail elderly is needed. After 4 years, the cumulative rate of bleeding causing discontinuation of anticoagulation therapy in this usual-care study of frail older patients was not alarmingly higher than in other usual-care studies.

Discrepancies in reported drug use in geriatric outpatients: relevance to adverse events and drug-drug interactions.

BACKGROUND Increased age is associated with polypharmacy. Polypharmacy is a risk factor for severe adverse drug reactions (ADRs) and is associated with an increased risk of mortality. OBJECTIVES The main goal of the current study was to describe the frequency and relevancy of discrepancies in drug use in Dutch geriatric outpatients as reported by the patients and their caregivers, documented by the referring general practitioner (GP), and registered by the public pharmacy. The frequency of medication discrepancy adverse patient events (MDAPEs) was also recorded. In addition, possible contributing factors-such as increasing age, cognitive status and depressive symptoms, the number of medications used, the number of physicians visited by the patient, and the presence of a caregiver to supervise medication use-were studied. METHODS This was a prospective descriptive study conducted at the geriatric outpatient clinic of a teaching hospital. Between January 1 and May 1, 2005, consecutive patients were included if they were aged >65 years, reported use of > or =1 medication, and if they could understand the goals and consequences of participating in the study. The medications described by geriatric patients and their caregivers were compared with the drugs listed by their GP. The pharmacies of the referred patients were asked to send a description of the drugs distributed in the 6 months preceding the patients visit to the geriatric outpatient clinic. The classification of ADRs and undertreatment as clinically relevant was done by study investigators who were blinded for the presence of discrepancy. RESULTS A total of 120 outpatients were included. The mean (SD) age of the study patients was 82.3 (6.8) years; 71.7% were women. Of the 120 patients, 113 patients (94.2%) reported taking >1 drug and 88 (73.3%) were prescribed > or =4 drugs. At least 1 discrepancy between the medication lists of the patients, GP, or pharmacy was present in 104 of the 120 patients (86.7%). In 90 patients (75.0%), there was > or =1 discrepancy between the medication reported by the patient and the GP. Patients with > or =1 discrepancy reported taking a higher mean number of drugs and had more prescribing physicians in addition to their GP. Twenty-nine patients (24.2%) experienced an MDAPE involving the use of drugs the GP had not correctly described in the letter of referral. The pharmacy was unaware of the use of medication involved in an MDAPE in 2 patients. CONCLUSIONS Geriatricians should assume that the medication lists supplied by GPs are incomplete or incorrect, and be aware that in approximately 25% of patients, symptoms may be caused by medication use inaccurately described in the referral. Reports by the community pharmacy may supply valuable additional information. Because there are also discrepancies between patients and pharmacies, medication use from a database-with data from prescribing physicians and pharmacy systems-will still have to be confirmed by the patient.

Cardiometabolic risk variables in overweight and obese children: a worldwide comparison

The growing prevalence rate of pediatric obesity, which is frequently accompanied by several cardiometabolic risk factors, has become a serious global health issue. To date, little is known regarding differences for cardiometabolic risk factors (prevalence and means) in children from different countries. In the present review, we aimed to provide a review for the available evidence regarding cardiometabolic risk factors in overweight pediatric populations. We therefore provided information with respect to the prevalence of impaired fasting glucose/impaired glucose tolerance, high triglycerides, low HDL-cholesterol and hypertension (components of the metabolic syndrome) among cohorts from different countries. Moreover, we aimed to compare the means of glucose and lipid levels (triglycerides and HDL-cholesterol) and systolic/diastolic blood pressure values. After careful selection of articles describing cohorts with comparable age and sex, it was shown that both prevalence rates and mean values of cardiometabolic risk factors varied largely among cohorts of overweight children. After ranking for high/low means for each cardiometabolic risk parameter, Dutch-Turkish children and children from Turkey, Hungary, Greece, Germany and Poland were in the tertile with the most unfavorable risk factor profile overall. In contrast, cohorts from Norway, Japan, Belgium, France and the Dominican Republic were in the tertile with most favorable risk profile. These results should be taken with caution, given the heterogeneity of the relatively small, mostly clinical cohorts and the lack of information concerning the influence of the values of risk parameters on true cardiometabolic outcome measures in comparable cohorts. The results of our review present a fair estimation of the true differences between cardiometabolic risk profiles among pediatric cohorts worldwide, based on available literature.

The effect of hyperthyroidism on procoagulant, anticoagulant and fibrinolytic factors

Several coagulation and fibrinolytic parameters appear to be affected by thyroid hormone excess; however, the net effect on the haemostatic system remains unclear. We aimed to update our previous review and systematically summarise and meta-analyse the data by assessing the effects of thyrotoxicosis on the coagulation and fibrinolytic system in vivo . Data sources included MEDLINE (2006-2012), EMBASE (2006-2012), and reference lists. The sources were combined with our previous search containing studies from 1980-2006. Eligible studies were all observational or experimental studies. Two investigators independently extracted data and rated study quality. Weighted mean proportion and 95% confidence intervals were calculated and pooled using a fixed and a random-effects model. A total of 29 articles consisting of 51 studies were included, as in several articles more than one study was described. We included four intervention (before and after treatment in hyperthyroid patients), five cross-sectional (hyperthyroid subjects and euthyroid controls), and four experimental (before and after use of thyroid hormone in euthyroid subjects) medium/high quality studies for meta-analysis. We found that thyrotoxicosis shifts the haemostatic balance towards a hypercoagulable and hypofibrinolytic state with a rise in factors VIII and IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1. This was observed in endogenous and exogenous thyrotoxicosis, and in subclinical as well as overt hyperthyroidism. We conclude that both subclinical and overt hyperthyroidism induce a prothrombotic state, which is therefore likely to be a risk factor for venous thrombosis.

Ethnic differences in cardiometabolic risk profile in an overweight/obese paediatric cohort in the Netherlands: a cross-sectional study

BackgroundDifferences in prevalence of cardiometabolic risk factors between different ethnic groups are largely unknown. We determined the variation in cardiometabolic risk profile according to ethnicity in a cohort overweight/obese Dutch children.MethodsAn oral glucose tolerance test was performed in 516 overweight/obese Dutch children of multi-ethnic origin, attending an obesity out-patient clinic of an urban general hospital (mean age 10.6 ± 3.2; 55.2% boys). Anthropometric parameters and blood samples were collected, and the prevalence of (components of) the metabolic syndrome (MetS) and insulin resistance were determined in each ethnic group.ResultsMajor ethnic groups were Dutch native (18.4%), Turkish (28.1%), and Moroccan (25.8%). The remaining group (27.7%) consisted of children with other ethnicities. Turkish children had the highest mean standardized BMI compared to Dutch native children (P < 0.05). As compared to Moroccan children, they had a higher prevalence of MetS (22.8% vs. 12.8%), low HDL-cholesterol (37.9% vs. 25.8%), hypertension (29.7% vs. 18.0%) and insulin resistance (54.9% vs. 37.4%, all P < 0.05). Although Turkish children also had higher prevalences of forementioned risk factors than Dutch native children, these differences were not statistically significant. Insulin resistance was associated with MetS in the Turkish and Moroccan subgroup (OR 6.6; 95%CI, 2.4–18.3 and OR 7.0; 95%CI, 2.1–23.1, respectively).ConclusionIn a Dutch cohort of overweight/obese children, Turkish children showed significantly higher prevalences of cardiometabolic risk factors relative to their peers of Moroccan descent. The prospective value of these findings needs to be established as this may warrant the need for differential ethnic-specific preventive measures.

Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study.

Summary.  Background: Several hemostatic abnormalities have been reported in hyperthyroidism, but the overall effect of thyroid hormone excess on coagulation and fibrinolysis is unclear. Objective: Our aim was to assess whether the use of supraphysiological doses of levothyroxine leads to coagulation activation and inhibition of fibrinolysis. Patients and methods: Healthy volunteers were randomized to receive levothyroxine or no medication for 14 days with a washout period of at least 28 days in a crossover design. To study the effects of different degrees of thyroid hormone excess, 16 participants received levothyroxine in a dose of 0.3 mg per day, and 12 received levothyroxine 0.45 or 0.6 mg per day depending on body weight. Several variables of coagulation and fibrinolysis were measured. Results: Levels of von Willebrand factor activity (VWF:RiCo) and antigen (VWF:Ag), factor (F) VIII, plasminogen activator inhibitor‐1 (PAI‐1) and clot‐lysis time were slightly higher after levothyroxine 0.3 mg per day than after the control situation, but only levels of VWF showed a significant increase from baseline. After levothyroxine 0.45 or 0.6 mg per day, levels of fibrinogen increased by 17%, VWF activity by 24%, VWF antigen by 26%, FVIII by 19%, FIX by 14%, FX by 7%, PAI‐1 by 116% and clot‐lysis time by 14%, and activated partial thromboplastin time decreased by 3%; all were significant changes compared with the control situation. We did not observe clear evidence of coagulation activation. Conclusions: Our data suggest that thyroid hormone excess increases coagulation factor levels and inhibits fibrinolysis in a dose‐dependent fashion. This implies an increased risk of venous thrombosis during hyperthyroidism.

Changes in Under-Treatment after Comprehensive Geriatric Assessment An Observational Study

AbstractBackground Under-treatment is frequently present in geriatric patients. Because this patient group often suffer from multiple diseases, polypharmacy (defined as the concomitant chronic use of five or more drugs) and contraindications to indicated drugs may also frequently be present. Objective To describe the prevalence of under-treatment with respect to frequently indicated medications before and after comprehensive geriatric assessment (CGA) and the prevalence of contraindications to these medications. Patients and Methods The geriatric outpatients evaluated in this study had previously been included in a prospective descriptive study conducted in 2004. Demographic data, medical history, co-morbidity and medication use and changes were documented. The absence of drugs indicated for frequently under-treated conditions before and after CGA was compared. Under-treatment was defined as omission of drug therapy indicated for the treatment or prevention of 13 established diseases or conditions known to be frequently under-treated. Co-morbid conditions were independently classified by two geriatricians, who determined whether or not a condition represented a contraindication to use of these drugs. Results In 2004, 807 geriatric outpatients were referred for CGA. Of these, 548 patients had at least one of the 13 selected diseases or conditions. Thirty-two of these patients were excluded from the analysis, leaving 516 patients. Before CGA, 170 of these patients were under-treated (32.9%); after CGA, 115 patients (22.3%) were under-treated. Contraindications were present in 102 of the patients (19.8%) and were more frequent in under-treated patients. After CGA, mean drug use and the prevalence of polypharmacy increased. Although 393 drugs were discontinued after CGA, the overall number of drugs used increased from 3177 before CGA to 3424 after CGA. Five times more drugs were initiated for a new diagnosis than for correction of under-treatment. Conclusions Under-treatment is significantly reduced after CGA. Patients with contraindications to indicated medicines are more frequently under-treated. CGA leads to an increase in polypharmacy, mainly because of new conditions being diagnosed and despite frequent discontinuation of medications.

High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis: the MEGA study

Thyroid hormone affects the coagulation system, but its effect on clinical disease is not clear. We determined the associations of levels of free thyroxine (FT4), thyroid‐stimulating hormone (TSH) and anti‐thyroid peroxidase antibodies (antiTPO) with levels of coagulation factors and the risk of venous thrombosis.

Identifying the metabolic syndrome in obese children and adolescents: do age and definition matter?

OBJECTIVES To assess the prevalence of the metabolic syndrome (MetS) in overweight/obese children and adolescents of an out-patient clinic, and to compare two definitions of MetS in adolescents. METHODS In total, 528 overweight / obese children (3-16 years), of multi-ethnic origin, underwent an oral glucose tolerance test, blood collections and anthropometric measurements. In children <10 years, MetS was assessed according to child-specific cut-off values (MetS-child). In adolescents, MetS-child and MetS-adolescent (the recommendation of the International Diabetes Federation for adolescents) were compared. RESULTS The prevalence of MetS-child within the cohort (median age 11.3, range 3.1-16.4 yrs) was 18.6% (children <10 years vs. adolescents: 14.1% vs. 20.7%, P=0.073). Insulin resistance was present in 47.7% (children <10 years vs. adolescents: 21.8% vs. 60.1%, P<0.001). MetS-child was highly prevalent, and not statistically significant between age groups. In adolescents, the prevalence of MetS-adolescent was higher than MetS-child (33.2% vs. 20.7%, P<0.001). The agreement between the MetS definitions was moderate (kappa =0.51), with the agreement for the MetS-criteria for abnormal lipid levels being substantial to very good (kappa =0.71 to 0.80). CONCLUSIONS MetS-child was highly prevalent in overweight/obese children and adolescents. A higher prevalence of MetS according to adolescent- as compared to child-specific criteria was found.

Thrombin-activatable fibrinolysis inhibitor in hypothyroidism and hyperthyroxinaemia

Endocrine disorders affect both the coagulation and fibrinolytic systems, and have been associated with the development of cardiovascular diseases. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a link between coagulation and the fibrinolytic system. The aim of this study was to determine the effect of thyroid hormone excess and deficiency on TAFI levels and function. The effect of hyperthyroxinemia on TAFI was studied in healthy volunteers who were randomised to receive levothyroxine or no medication for 14 days in a crossover design. The effect of hypothyroidism on TAFI was studied in a multicentre observational cohort study. Blood was drawn before treatment of patients with newly diagnosed hypothyroidism and when euthyroidism was achieved. Plasma clot-lysis times, activated TAFI (TAFIa)-dependent prolongation of clot-lysis and TAFI levels were measured. Thyroid hormone excess resulted in a hypofibrinolytic condition and in an enhanced TAFIa-dependent prolongation of clot lysis. A trend towards decreased plasma TAFI levels was observed in healthy volunteers who used levothyroxine. Hypothyroidism resulted in hyperfibrinolysis and a reduced TAFIa-dependent prolongation of clot lysis. In conclusion, alterations of TAFIa-dependent prolongation of clot lysis in patients with thyroid disorders may cause an impaired haemostatic balance. The disturbed haemostatic balance in patients with hyperthyroidism might make them prone to thrombosis, while the risk for bleeding may increase in patients with hypothyroidism.