Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism

The efficacy and safety of vitamin K antagonists (VKA) are related to the actual level of anticoagulation (given as the international normalized ratio, INR). It is often difficult to maintain an optimal INR over time. We assessed the clinical impact of the individual time spent within INR target range (ITTR) in 2304 consecutive patients with venous thromboembolism. Annual incidences of recurrent thromboembolism and major bleeding were 6.2% and 2.8% respectively. The relative risk (RR) of thromboembolism was 4.5 [95% confidence interval (CI) 3.1-6.6, P < 0.001] at INR < 2.0, for major bleeding it was 6.4 (2.5-16.1, P < 0.001) at INR > 5.0, compared with INR 2.0-3.0. Patients with ITTR < 45% were at higher risk than those with ITTR > 65% (RR 2.8, 1.9-4.3, P < 0.001), while no difference was demonstrated comparing ITTR 45-65% and ITTR > 65% (RR 1.2, 0.7-1.8, P = 0.54). Annual incidences of recurrent thromboembolism were 16.0%, 4.9% and 4.6% at ITTR < 45%, 45-60% and >65% respectively. For major bleeding these were 8.7%, 2.1% and 1.9% respectively. ITTR < 37% during the first 30 treatment days was highly predictive for the total treatment time ITTR < 45% (RR 24.2, 13.5-43.1, P < 0.001). In conclusion, ITTR can be used to identify patients on VKA at risk of recurrent thromboembolism or major bleeding. Since the 30-d ITTR is highly predictive for total treatment ITTR, these patients can be identified soon after start of treatment.     

Wetland management according to the Water Framework Directive 2000/60

The Water Framework Directive sets the basis for a new water management regulatory perspective, which is of immediate relevance to wetlands. Up to recently, these were perceived solely as marginal habitats, fulfilling a specific role in the conservation of rare and protected species. The principles established by the Directive for the evaluation of the ecological status of significant water bodies relate directly to the relevance of the hydromorphological elements which are part of them, including ecotonal and riparian habitats, as well as other humid habitats connected to the main network. By recognising the moderation role played by wetlands in relation to the impacts affecting the river basin, a new interesting opportunity opens up. This new perspective welcomes forms of management which maximise the environmental quality of riparian areas, of small ponds and of all those situations which are conducive to the restoration of natural processes leading to the control of discharge and pollution loads.     

Efficacy of erythropoietin administration in the treatment of anemia immediately after renal transplantation

Anemia negatively impacts cardiovascular comorbidity and hospitalization. In animals, recombinant erythropoietin (RhuEPO) leads to faster recovery after acute tubular necrosis. This study evaluates the effect of RhuEPO (Recormon, Hoffman-La Roche, Basel, Switzerland) on the correction of anemia and kidney function after renal transplantation. Patients receiving a renal transplant were randomized to receive or not receive RhuEPO 100 U/kg three times per week if the hemoglobin (Hb) level was less than 12.5 g/dL. The time to reach an Hb level greater than 12.5 g/dL was 66.5+/-14.5 days versus 52.6+/-23.7 days in the non-EPO and EPO groups, respectively (P=0.05). After 3 months, Hb levels were not different between the non-EPO and EPO groups (12.6+/-1.5 g/dL vs. 12.0+/-1.5 g/dL, respectively), although there was a higher increase in the EPO group (4.1+/-1.1 g/dL vs. 3.2+/-1.1 g/dL, P=0.02). In a Cox regression analysis, EPO use (relative risk 7.2, P=0.004) and dose (relative risk=0.63, P=0.04) were retained as independent variables predicting the time to reach an Hb level greater than 12.5 g/dL. In the EPO group, 14 of 22 patients reached the target Hb level of more than 12.5 g/dL versus 12 of 18 patients in the non-EPO group (P=not significant). Serum creatinine levels were not different between groups. RhuEPO in the immediate posttransplantation period seems to have no relevant clinical impact on the correction of anemia. There was no difference in the evolution of serum creatinine levels. In view of the cost, the use of RhuEpo in the posttransplantation period should be limited to high-risk patients.     

"A thoughtful and experienced physician": William Munk and the care of the dying in late Victorian England

William Munk (1816-1898) qualified as a physician in 1837 and practiced in London for more than 60 years. Munk became well known in the medical profession during the second half of the nineteenth century for his emphasis on the importance of narcotics for the relief of pain in incurable disease and was also a recognized authority on smallpox. In addition to his medical practice Munk was the Harveian Librarian of the Royal College of Physicians for almost 40 years and, among other biographical works, single-handedly produced the Roll of the Royal College of Physicians of London 1518-1700. His most significant clinical publication, Euthanasia, or Medical Treatment in Aid of an Easy Death, appeared toward the end of his career and was enthusiastically received by the medical and nursing professions. This paper gives a more detailed account of Munk's life and work than has yet appeared and focuses in particular on the contents and contemporary influence of his important late nineteenth century treatise on the care of the dying.     

Design and methodology of the COACH study: a multicenter randomised Coordinating study evaluating Outcomes of Advising and Counselling in Heart failure

BACKGROUND: While there are data to support the use of comprehensive non-pharmacological intervention programs in patients with heart failure (HF), other studies have not confirmed these positive findings. Substantial differences in the type and intensity of disease management programs make it impossible to draw definitive conclusions about the effectiveness, optimal timing and frequency of interventions. AIMS: 1. To determine the effectiveness of two interventions (basic support vs. intensive support) compared to 'care as usual' in HF patients, on time to first major event (HF readmission or death), quality of life and costs. 2. To investigate the role of underlying mechanisms (knowledge, beliefs, self-care behaviour, compliance) on the effectiveness of the two interventions. METHODS: This is a randomised controlled trial in which 1050 patients with heart failure will be randomised into three treatment arms: care as usual, basic education and support or intensive education and support. Outcomes of this study are; time to first major event (HF hospitalisation or death), quality of life (Minnesota Living with HF Questionnaire, RAND36 and Ladder of Life) and costs. Data will be collected during initial admission and then 1, 6, 12, and 18 months after discharge. In addition, data on knowledge, beliefs, self-care behaviour and compliance will be collected. RESULTS: The study started in January 2002 and results are expected at the end of 2005. CONCLUSIONS: This study will help health care providers in future to make rational and informed choices about which components of a HF management program should be expanded and which components can possibly be deleted.     

Coronary vasomotor response is related to the angiographic extent of coronary sclerosis in patients with stable angina pectoris

Disturbed vasomotor function in coronary arteries has clinical importance in early stages of coronary artery disease (CAD), as it may contribute to the potential risk for an ischaemic coronary event. In the present study, we have investigated the relationship between coronary vasomotor function and the extent of CAD. The response to acetylcholine and nitrate infusion was assessed by quantitative coronary angiography. The extent of CAD was categorized into two groups: minor CAD (normal coronary arteries and vessel wall irregularities) and significant CAD (one-, two- and three-vessel disease). A total of 277 patients with stable angina pectoris, referred for a first diagnostic coronary angiography, were eligible for analysis (mean age 57 years, 61% male). The response to nitrate was significantly impaired in patients with significant CAD ( P <0.001). On the other hand, the response to acetylcholine was not different between the two groups ( P =0.12); however, a trend between the response to acetylcholine and the extent of CAD was observed in patients without a previous infarction ( P =0.07), which was a significant interaction variable. Furthermore, a significant relationship between coronary vasomotor response and the number of cardiovascular risk factors was observed ( P <0.05). In conclusion, in a heterogeneous group of patients, coronary vasomotor function measured by nitrate infusion was more strongly associated with the extent of CAD and the number of risk factors than the response to acetylcholine. These data suggest that, in patients with advanced atherosclerosis or multiple risk factors, the vasomotor dysfunction is not solely restricted to the endothelium.     

Evidence for a 5-HT2A receptor mode of action in the anxiolytic-like properties of DOI in mice

DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] displays a high affinity for the rat 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi 7.3, 7.4 and 7.8, respectively) and acts as an agonist. DOI (0.5-4 mg/kg, i.p. 30 min pre-test) increased the number of punished passages in the mouse four plates test (FPT). The anti-punishment action of DOI (1 mg/kg, i.p. 30 min pre-test) was abolished by prior treatment with the selective 5-HT2A receptor antagonist SR 46949B (0.1 and 1 mg/kg, i.p. 45 min pre-test) but not by the selective 5-HT2C receptor antagonist RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor the selective 5-HT2C/2B receptor antagonist SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). An anxiolytic-like action was also observed for DOI (1 mg/kg) in the elevated plus maze (EPM). The anxiolytic-like action of DOI (1 mg/kg, i.p. 30 min pre-test) was antagonised by pre-treatment with SR 46949B (0.125 and 0.5 mg/kg, i.p. 45 min pre-test) but not by RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). In conclusion, DOI produced an anxiolytic-like profile in the mouse FPT and EPM. These effects are likely to be 5-HT2A receptor mediated.     

Kinetics of the uptake and distribution of the dopamine D(2,3) agonist (R)-N-[1-(11)C]n-propylnorapomorphine in brain of healthy and MPTP-treated Göttingen miniature pigs

The binding of radioligand agonists to dopamine receptors in living brain can be informative about the abundance of receptors which are coupled to intracellular second messenger systems. Therefore, we developed a radiosynthesis for the dopamine D(2,3) partial agonist (R)-N- [1-(11)C]n-propylnorapomorphine ([(11)C]NPA). The uptake of this tracer in brain of anesthetized G?ttingen miniature pigs was recorded by positron emission tomography (PET) and analyzed by compartmental analysis using the metabolite-corrected arterial input, and using reference tissue methods. [(11)C]NPA had a blood-brain unidirectional clearance of approximately 0.35 ml g(-1) min(-1) and an apparent distribution volume of 6 ml g(-1) in cerebellum. The ligand had a binding potential of 1.5 in striatum, comparable to that reported previously for the receptor antagonist [(11)C]raclopride in the same strain of animals. Significant binding was detected in the hypophysis, thalamus, and medial forebrain bundle. The binding in striatum was of comparable magnitude in normal pigs and in pigs with a documented 50% dopamine depletion produced by MPTP-intoxication. Deep brain stimulation of the subthalamus was without conspicuous effect on the binding of [(11)C]NPA in vivo. Results of this preliminary study indicate that this tracer meets many requirements for assaying dopamine agonist binding sites by PET.