Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarinic metabolism. Variant alleles, CYP2C9*2 and CYP2C9*3, have been related to decreased enzymatic activity, but their clinical ...relevance in acenocoumarol metabolism has not been established. We investigated CYP2C9 polymorphisms in relation to acenocoumarol dose requirement, stability of anticoagulation and bleeding.
CYP2C9 genotyping was performed in 325 acenocoumarol-treated patients (INR target between 2.0 and 3.0) and in an additional group of 84 patients with repeated bleeding.
Patients with the wild-type CYP2C9*1/*1 genotype (n=169) required a higher maintenance dose of acenocoumarol (17.1 8.7 mg/week) than did patients with the CYP2C9*2 (14.6 6.4 mg/week, p<0.05, N=97) or the CYP2C9*3 allele (11.2 6.2 mg/week, p<0.001, n=59). Out of 170 patients requiring a low-dose of acenocoumarol (<or= 2 mg/day), 27.1% carried the CYP2C9*3 allele, while among the patients requiring higher doses, 8.4% had CYP2C9*3 (OR=4.77, 95% CI = 2.40-9.48, p<0.001 vs. 2C9*1/*1 patients). In the multivariate analysis, independent predictive variables for low-dose acenocoumarol requirements were age >70 years (OR=3.73, 95%CI=2.29-6.08, p<0.001), and the CYP2C9*3 allele (OR=4.75, 95%CI=2.36-9.55, p <0.001). Carriers of CYP2C9*3 spent less time within the therapeutic range (64.7 23.1%) than did patients with the CYP2C9*1/*1 genotype (75.1 22.0%, p<0.01), and more frequently had an INR >4.5 at the initiation of treatment (43.9% vs.11.6%, p<0.001), but did not show repeated bleeding more frequently (19.0% vs.15.5%, p=NS).
CYP2C9*3 is related to lower acenocoumarol dose requirements, a higher frequency of over-anticoagulation at the initiation of therapy and an unstable anticoagulant response.
Background and importanceHospital discharge has been described as the care transition in which a major number of incorrect prescriptions occur. Discharge medication reconciliation aims to prevent ...discrepancies when comparing the inhospital with the discharge electronic prescription.Aim and objectivesTo assess the incidence of unjustified discrepancies during a medication reconciliation programme by pharmacists in complex chronic patients (CCP) at hospital discharge.Material and methodsThis was a cross sectional study where we assessed unjustified discrepancies between the inhospital prescriptions (which are summarised in the discharge report) and the electronic prescriptions for all CCP from April 2019 to May 2019. Data were obtained from the discharge report prescriptions and the electronic prescriptions. Unjustified discrepancies were assessed according to the medical records. CCP were defined as patients with chronic diseases and comorbidities due to socioeconomic, cultural and environmental situations interfering with the decision and the need to implement specific plans. Discrepancies were classified according to: (i) incomplete prescription, (ii) omission, (iii) incorrect dose, (iv) incorrect drug selection, (v) duplicity, (vi) incorrect timing and (vii) incorrect administration route.ResultsWe analysed the discharge prescriptions of 97 patients. Mean age was 81.7±9.7 years and 50 (51.6%) were women. Seventy-seven (79.4%) patients were admitted to medical wards and 20 (20.6%) to surgical wards. A total of 272 discrepancies were found in 77 (79.4%) patients with a mean of 2.8±2.8 discrepancies per patient: 114 (41.9%) discrepancies were related to incomplete prescription, 70 (25.7%) to omission, 67 (24.6%) to incorrect dose, 10 (3.7%) to incorrect drug selection, 7 (2.6%) to duplicities, 3 (1.1%) to incorrect timing and 1 (0.4%) to incorrect administration route.Conclusion and relevanceWe found that about 80% of patients presented at least one unjustified discrepancy. Medication reconciliation is a major component of safe patient care in any environment. Therefore, education of healthcare professionals and implementation of tools such as electronic reconciliation software could be useful to improve safety.References and/or acknowledgementsNo conflict of interest.
Background and importanceIt is estimated that asthma affects 4.9% of adults in Spain and 3.9% are classified as severe uncontrolled asthma (SUA). Omalizumab, mepolizumab, reslizumab and benralizumab ...are monoclonal antibodies indicated in the treatment of SUA in adults.Aim and objectivesTo analyse the effectiveness and improvement in quality of life in patients with SUA treated with monoclonal antibodies in a second level hospital.Material and methodsA retrospective observational study was conducted of all patients with SUA who received monoclonal antibody therapy from August 2011 to September 2019. Age, gender and clinical data (treatment duration, ingestion of oral corticosteroids (OCS), asthma control test (ACT), presence of exacerbations requiring OCS and hospitalisations related to asthma) were recorded before starting immunotherapy and at the last follow-up visit. Effectiveness was evaluated as a reduction in OCS, exacerbations and/or hospitalisations. ACT was used to evaluate improvement in quality of life, with a score of at least 20 considered good control of asthma.ResultsForty-eight patients were included, 70.8% (n=34) were women, mean age was 56 years (23–79), and 75% (n=36) were treated with omalizumab, 18.7% (n=9) with mepolizumab, 4.2% (n=2) with reslizumab and 2.1% (n=1) with benralizumab. Mean duration of treatment was 31, 9, 8 and 1 month, respectively. Effectiveness was not evaluated in three patients due to lack of information. Treatment was discontinued in 7 patients for inefficacy, 3 for tolerance, 1 for adherence and 1 for hospital referral. Three patients were switched from omalizumab to mepolizumab during the study. Before starting immunotherapy, 24.3% (n=10) of patients had ACT >20, and in the previous year 53.5% (n=23) took OCS, 83.7% (n=36) had exacerbations requiring OCS and 37.2% (n=16) required at least one hospitalisation due to an exacerbation. After treatment, the last follow-up results were 65.1% (n=28), 23.3% (n=10), 44.7% (n=17) and 5.3% (n=2), respectively.Conclusion and relevanceImmunotherapy was effective in most cases, reducing exacerbations and hospitalisations in SUA. It also allowed discontinuation of OCS therapy. The improvement in quality of life was proved with the increase in ACT score, despite its subjectivity.References and/or acknowledgementsNo conflict of interest.
BackgroundAntipsychotics (APs) are commonly used to manage neuropsychiatric symptoms (NPS) in the elderly with dementia (approximately 48% of the elderly with dementia are treated with APs), even ...though several large studies have demonstrated an association between AP treatment and increased morbidity and mortality in people with dementia.PurposeThe aim of this study was to review the scientific literature of the use of AP in the elderly with dementia and to propose an algorithm to assist in decision-making regarding the withdrawal of APs.Material and methodsA computerised literature search (MEDLINE: 1966 to July 2017, EMBASE: 1982 to July 2017) was used to locate relevant literature. The following terms were used in the MESH database and EMTREE thesaurus: aged, antipsychotic agents, behavioural symptoms and dementia. The information and recommendations of full references were extracted to perform an algorithm represented on paper in a flow-chart form. In the algorithm we define non-pharmacological interventions, NPS and signs and symptoms of AP withdrawal. We use the Neuropsychiatric Inventory Questionnaire (NPI-Q) to score the severity of the NPS.ResultsEarlier studies of APs used in the elderly with dementia suggest that, in most elderly demented patients, APs can be withdrawn with no effect on behaviour. These patients are likely to benefit from the algorithm we propose to assist clinicians with in the withdrawal of APs (Algorithm 1). Although prolonged treatment in specific circumstances may be advisable in clinical practice, the general advice is to discontinue APs after 12 weeks in cases of agitation or psychosis associated with dementia based on weak and conflicting evidence regarding long-term efficacy. A gradual tapering strategy is to reduce dosage by 25% to 50% every 2 weeks and to end treatment 2 weeks after administering the lowest dose.ConclusionInformation gathered in this review raises the need to establish safe and effective pharmacological approaches to AP prescription for the demented elderly with NPS. We have described an algorithm consisting of three main steps presented in the form of a flowchart that draws on AP withdrawal approaches recommended in both dementia and care guidelines, and which can assist clinicians in the withdrawal of APs.No conflict of interest
In 2,000 consecutive stroke patients collected in a prospective hospital-based stroke registry over a 10-year period, we assessed whether stroke in men and women was different in respect to vascular ...risk factors, clinical features and natural history. The frequency of the different variable in men and women was analyzed by means of univariate analysis and logistic regression models. Women accounted for 48% of the study population (n = 967) and were older than men (mean age 75 vs. 69 years, p < 0.001). In the age group of 85 years or older, stroke was more frequent in women than in men (69.8 vs. 30.2%, p < 0.001). Women showed a higher frequency of cardioembolic infarction and a lower occurrence of lacunar infarction and stroke of undetermined cause than men. In-hospital mortality (17.4 vs. 13.3%) and length of hospital stay (19.6 vs. 16.7 days) was significantly higher (p < 0.001) in women than in men. In the model based on demographic variables and cardiovascular risk factors, obesity, heart failure, atrial fibrillation and age were significant predictors of stroke in women, while intermittent claudication, ischemic heart disease, chronic obstructive pulmonary disease, cigarette smoking and alcohol abuse were predictors in male sex. Hypertension and limb weakness were predictors for stroke in women, and absence of neurological deficit at hospital discharge, lacunar syndrome and ataxia were predictors in men in the models based on all variables. Women differ from men in the distribution of risk factors and stroke subtype, stroke severity and outcome. Differences in stroke pathology and/or differences in functional anatomy or plasticity of the brain between sexes may account for these findings.
Increased risk of bleeding during oral anticoagulant (OA) treatment may be related to mutations in the precursor of coagulation factor IX. Missense mutations at Ala-10 (Ala-10Thre and Ala-10Val) in ...the factor IX propeptide lead to impaired carboxylation of factor IX. When patients carrying these mutations are treated with coumarins, functional factor IX levels decrease significantly, leading to an excessively prolonged activated partial thromboplastin time (aPTT) and an increased bleeding risk. Mutations at Ala-10 have been described in northern-European patients, but it is not known whether geographical differences play a role in the prevalence of these mutations. We aimed to analyze the prevalence of mutations at Ala-10 in factor IX in southern-European patients on OA treatment. Patients attending the Oral Anticoagulant Unit of the Hospital Clinic were prospectively included. The aPTT was determined at their normal International Normalized Ratio (INR) control. When the aPTT was excessively prolonged for the INR value, determination of factor IX and genotyping for Ala-10 mutations was performed. A total of 2360 patients were included (1289 men, 1071 women; mean age, 70.5 +/- 12.1 years). Twenty-four patients (16 men, eight women; mean age, 61.0 +/- 16.2 years) had an aPTT over that expected for the INR. The mean aPTT was 69.6 +/- 16.2 s. Only one patient presented with a factor IX level lower than 10%. None of the 24 patients carried mutations at Ala-10. Mutations at Ala-10 in factor IX were non-existent in the southern-European population analyzed, and thus, do not represent a relevant cause of bleeding during OA treatment.
Pharmacological strategies aimed at the prevention of thrombotic complications are in continuous development. Argatroban is a synthetic small molecule derived from l-arginine with specific ...antithrombotic activity. Argatroban is a direct thrombin inhibitor that binds avidly and reversibly to the catalytic site of thrombin and that does not require other cofactors to exert its antithrombotic action. Due to its selective inhibitory mechanism, argatroban blocks both circulating and clot-bound thrombin. A rapid onset of its anticoagulant action is achieved after intravenous administration. The short elimination half-life of argatroban (52+/-16 minutes) ensures a rapid restoration of hemostasis upon cessation of treatment. Argatroban produces a predictable dose response, and its anticoagulant actions can be monitored easily through the routine coagulation tests activated partial thromboplastin time (aPTT) and activated clotting time (ACT). The specific mechanism of action and favorable pharmacokinetic profile of argatroban suggest that it could be beneficial in all indications where other intravenous anticoagulants are used. Results from clinical studies performed to date show that, when administered to patients with heparin-induced thrombocytopenia (HIT) or HIT with thrombosis (HITTS) in two large-scale, nonrandomized, prospective trials, argatroban reduced a combined endpoint of morbidity and mortality when compared with historical controls. Argatroban was well tolerated in clinical trials of patients with HIT and caused no increase in bleeding risk compared with historical controls. Argatroban does not induce the formation of antibodies that can neutralize its anticoagulant effect, prolong its half-life or enhance its activity. The U.S. Food and Drug Administration has approved the use of this drug as an alternative antithrombotic treatment for patients with HIT as well as for patients with or at risk for HIT undergoing percutaneous coronary interventions. In 2004 (Sweden), 2005 (Germany, the Netherlands, Austria and Iceland) and 2006 (Denmark) argatroban was approved for anticoagulation in adult patients with heparin-induced thrombocytopenia type II who require parenteral antithrombotic therapy.
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