Safety relevant knowledge of orally anticoagulated patients without self-monitoring: a baseline survey in primary care.

BACKGROUND: Effective and safe management of oral anticoagulant treatment (OAT) requires a high level of patient knowledge and adherence. The aim of this study was to assess patient knowledge about OAT and factors associated with patient knowledge. METHODS: This is a baseline survey of a cluster-randomized controlled trial in 22 general practices with an educational intervention for patients or their caregivers. We assessed knowledge about general information on OAT and key facts regarding nutrition, drug-interactions and other safety precautions of 345 patients at baseline. RESULTS: Participants rated their knowledge about OAT as excellent to good (56%), moderate (36%) or poor (8%). However, there was a discrepancy between self-rated knowledge and evaluated actual knowledge and we observed serious knowledge gaps. Half of the participants (49%) were unaware of dietary recommendations. The majority (80%) did not know which non-prescription analgesic is the safest and 73% indicated they would not inform pharmacists about OAT. Many participants (35-75%) would not recognize important emergency situations. After adjustment in a multivariate analysis, older age and less than 10 years education remained significantly associated with lower overall score, but not with self-rated knowledge. CONCLUSIONS: Patients have relevant knowledge gaps, potentially affecting safe and effective OAT. There is a need to assess patient knowledge and for structured education programs. TRIAL REGISTRATION: Deutsches Register Klinischer Studien (German Clinical Trials Register): DRKS00000586.Universal Trial Number (UTN U1111-1118-3464).

Practice nursed-based, individual and video-assisted patient education in oral anticoagulation--protocol of a cluster-randomized controlled trial.

BACKGROUND: Managing oral anticoagulant treatment (OAT) is a challenge for patients and primary care providers. It requires a high level of patient knowledge and adherence. Studies have shown that insufficient adherence and a low level of patient knowledge about OAT are primary causes for complications. This trial is the first to evaluate the long-term effects of a complex practice nurse-based patient education program in comparison to a patient brochure only. METHODS AND DESIGN: This trial will be a cluster-randomized controlled trial in 22 general practices (GPs) recruiting 360 patients with OAT. GPs will be randomized into an intervention group or a control group. A baseline questionnaire will assess pre-existing knowledge about OAT. The patients in the intervention group will be educated by a complex education program which consists of a video, a brochure and individual training by a practice nurse. The video gives information about OAT, nutrition, and instructions about how to manage critical situations. The brochure repeats the content of the video. After 4 to 6 weeks, the intervention will be recapitulated. The control group will receive the brochure only. After 6 months, questionnaires will be used in both groups to assess patient knowledge about OAT as well as patients' subjective feelings of safety. Separately, we will evaluate patient records, looking for documented complications and the time spent in the therapeutic range. DISCUSSION: This trial will start in January 2011. This trial will evaluate the long-term effectiveness of a video-assisted education program on patients with OAT in comparison to a patient information brochure. Most previous studies have evaluated knowledge directly after an educational intervention. Our trial will look for long-term differences in basic knowledge of OAT. We expect that our complex patient education program effectively increases long-term basic knowledge about OAT. Although the population of our study is too small to observe differences in adverse effects, we expect to discover differences in secondary outcomes, such as the time spent in the therapeutic range. TRIAL REGISTRATION: Deutsches Register Klinischer Studien (German Clinical Trials Register): DRKS00000586Universal Trial Number (UTN U1111-1118-3464).

A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat.

Umibecestat, an orally active ß-secretase inhibitor, reduces the production of amyloid beta-peptide that accumulates in the brain of patients with Alzheimer's disease. The echocardiogram effects of umibecestat, on QTcF (Fridericia-corrected QT), on PR and QRS and heart rate (HR), were estimated by concentration-effect modeling. Three phase I/II studies with durations up to 3 months, with 372 healthy subjects over a wide age range, including both sexes and 2 ethnicities, were pooled, providing a large data set with good statistical power. No clinically relevant effect on QTcF, PR interval, QRS duration, or HR were observed up to supratherapeutic doses. The upper bound of 90% confidence intervals of the ∆QTcF was below the 10 ms threshold of regulatory concern for all concentrations measured. Prespecified sensitivity analysis confirmed the results in both sexes, in those over and below 60 years, and in Japanese subjects. All conclusions were endorsed by the US Food and Drug Administration (FDA).

Two studies in one: A propensity-score-matched comparison of fingolimod versus interferons and glatiramer acetate using real-world data from the independent German studies, PANGAEA and PEARL.

BACKGROUND: This study compared outcomes following fingolimod or BRACE treatments (beta-interferons/glatiramer acetate) in patients with active MS (≥ 1 relapse in the previous year) following previous BRACE treatment. METHODS AND FINDINGS: Patients with active MS who previously received BRACE were identified from German prospective, observational studies, PANGAEA and PEARL. A novel methodology was developed to compare outcomes between propensity-score-matched cohorts (3:1 ratio) from the independent single-arm studies. Patients in PANGAEA (n = 1287) experienced 48% fewer relapses per year than those in PEARL (n = 429; annualized relapse rate ratio: 0.52; p < 0.001). The risk of 3-month or 6-month confirmed disability progression (CDP) was reduced in PANGAEA versus PEARL (3-month: 37% reduction; hazard ratio [HR], 0.63; p < 0.001; 6-month: 47% reduction; HR, 0.53; p < 0.001). A higher proportion of patients in PANGAEA (n = 1234) than PEARL (n = 401) were free from relapses and 3-month (65.7% vs 38.7%; p < 0.001) or 6-month (68.2% vs 39.2%; p < 0.001) CDP. The probability of confirmed disability improvement was higher in PANGAEA (n = 1163) than PEARL (n = 372; 3-month: 175% increase; HR, 2.75; p < 0.001; 6-month: 126% increase; HR, 2.26; p < 0.001). Patients in PANGAEA (n = 149) were less likely than those in PEARL (n = 307) to have taken sick leave (proportion with 0 days off work: 62.4% vs 44.6%; p = 0.0005). For change in disease severity from baseline (assessed by clinicians using the Clinical Global Impressions scale; PANGAEA, n = 1207; PEARL, n = 427), a larger proportion of patients had subjective improvement and a smaller proportion had worsening status in PANGAEA than PEARL (improvement: 28.2% vs 15.2%; worsening: 16.4% vs 30.4%; p < 0.0001). CONCLUSIONS: Fingolimod appears to be more effective than BRACE in improving clinical and physician-/patient-reported outcomes in individuals with active MS.

Anxiety- and novelty seeking-related personality traits and serotonin transporter gene polymorphisms.

The affection of human personality by the promoter and the intron 2 polymorphism in the serotonin transporter gene (SERT) is inconsistently reported. We aimed to clarify this situation by gender-specific haplotype-phenotype association. 98 women and 97 men completed the personality inventories NEO-PI-R and TPQ. The subjects were genotyped for the two SERT polymorphisms and the haplotypes were calculated. The short (S) and long (L) promoter alleles and the 12 and 10 repeat intron 2 alleles formed the haplotypes S 12, S 10, L 12 and L 10. In men, scores in the anxiety-related dimensions were higher in S 12 than in L 12 carriers. Opposite in direction, scores tended to be lower in S 10 than in L 10 carriers. In the novelty seeking-related dimensions, scores were higher in S 10 than in S 12 carriers. No association was observed in women. In conclusion, anxiety- and novelty seeking-related personality dimensions are differentially associated with different SERT haplotypes; the consistent restriction to men suggests common androgen regulation. Opposite trends with haplotypes including the same promoter alleles suggest contribution of group stratification to earlier inconsistent findings and call to further differentiate the molecular function and clinical implications of the SERT promoter polymorphism.

Multiple Sclerosis Therapy With Disease-Modifying Treatments in Germany: The PEARL (ProspEctive phArmacoeconomic cohoRt evaluation) Noninterventional Study Protocol.

BACKGROUND: Patients with multiple sclerosis (MS) require long-term therapy and have a wide variety of needs for health-related support. The efficacy and safety of MS therapy, as assessed by both clinicians and patients, are important parameters that need to be considered. However, few studies combine data on efficacy and safety outcomes with pharmacoeconomic data. OBJECTIVE: Here, we present the study design of the ProspEctive phArmacoeconomic cohoRt evaluation (PEARL), a prospective, multicenter, noninterventional cohort study on patients with relapsing-remitting MS (RRMS) treated with disease-modifying treatments (DMTs). METHODS: During a prospective observational phase of 24 months per patient, PEARL evaluated clinical and patient-perceived efficacy and safety measures, as well as pharmacoeconomic data on RRMS patients treated with DMTs-interferon beta and glatiramer acetate. Measurements of the patients' perceptions included the assessment of patient-reported quality of life, treatment satisfaction, and compliance. The study was planned to include 1800 outpatients from 180 German neurological practices who had continuously been treated with an approved DMT for at least 30 days. The primary statistical analyses of the PEARL study will be descriptive. Particular focus will be on specific subgroups, such as patients who switched DMTs during therapy and patients with disease worsening or disease activity. Subgroups will be compared using stratified analyses. RESULTS: Data collection for PEARL started in September 2010 and ended in July 2013. As of July 2015, the study is completed and is currently being analyzed and written up. CONCLUSIONS: PEARL is evaluating both the health status and resource utilization of RRMS patients treated with DMTs in Germany. The combination of pharmacoeconomic data with clinical and patients' self-perceived efficacy and safety outcomes will add useful information to the currently incomplete picture of the overall RRMS burden in Germany.

Combination treatment of fingolimod with antidepressants in relapsing-remitting multiple sclerosis patients with depression: a multicentre, open-label study - REGAIN.

OBJECTIVES: Approximately one in two patients with multiple sclerosis (MS) suffer from comorbid depression. The primary objective of this study was to evaluate the safety and tolerability of fingolimod and antidepressant combination in relapsing-remitting MS patients with mild-to-moderate depression. Efficacy outcome variables were quality of life (QoL), fatigue, disability and depression. METHODS: Patients received open-label fingolimod 0.5 mg over 2 weeks, followed by fingolimod plus citalopram (40 mg), fluoxetine (40 mg) or venlafaxine (150 mg) over 16 weeks. The antidepressant was selected at the physician's discretion. RESULTS: In total, 54 patients were recruited at 25 centres across Germany. No new safety signals (including cardiac) emerged compared with previous clinical studies. Adverse events (mostly mild-to-moderate) were reported in 43 patients. A total of three patients had serious adverse events and 10 discontinued the study. QoL (mean [95% confidence interval]) improved by 2.2 (-3.3, -1.2; Patient Reported Indices for MS questionnaire), fatigue by 8.2 (-13.1, -3.3; modified Fatigue Impact Scale) and depression by 6.3 (-8.4, -4.2; Hamilton Depression Scale) points. However, the results must be interpreted cautiously owing to limited patient numbers. CONCLUSIONS: Combination of fingolimod with antidepressant medication showed no unexpected safety signals. Patient-reported outcomes (QoL, disability, fatigue and depression) remained stable or improved.

Impact of mineralocorticoid receptor polymorphisms on urinary electrolyte excretion with and without diuretic drugs.

AIM: Polymorphisms in the mineralocorticoid receptor may affect urinary sodium and potassium excretion. We investigated polymorphisms in the MR gene in relation to urinary electrolyte excretion in two separate studies. PATIENTS & METHODS: The genotype-phenotype association was studied in healthy volunteers after single doses of bumetanide, furosemide, torsemide, hydrochlorothiazide, triamterene and after NaCl restriction. RESULTS: High potassium excretion under all conditions except torsemide, and high NaCl excretion after bumetanide and furosemide were associated with the A allele of the intron-3 polymorphism (rs3857080). This polymorphism explained 5-10% of the functional variation and in vitro, rs3857080 affected DNA binding of the transcription factor LHX4. CONCLUSION: rs3857080 may be a promising new candidate for research in cardiac and renal disorders and on antialdosteronergic drugs like spironolactone.

CYP2C9 polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide.

INTRODUCTION: According to in vitro data, torsemide (INN, torasemide) is a substrate of the genetically polymorphic enzyme cytochrome P450 (CYP) 2C9, but the impact of CYP2C9 polymorphisms on torsemide pharmacokinetics and pharmacodynamics has not been studied in humans. METHODS: A total of 36 healthy volunteers (12, 9, 1, 9, 3, and 2 carriers of CYP2C9 genotypes *1/*1 , *1/*2 , *2/*2 , *1/*3 , *2/*3 , and *3/*3 , respectively) received a single oral dose of 10 mg torsemide for pharmacokinetic and pharmacodynamic analysis. The effects of the CYP2C9 polymorphism on torsemide-induced urine volume and urinary elimination of sodium, potassium, chloride, and uric acid were measured during a salt-restricted diet. RESULTS: Median torsemide total oral clearance values were 3.4, 2.2, and 1.2 L/h in carriers of the CYP2C9 genotypes *1/*1 , *1/*3 , and *3/*3 , respectively, but there was no significant difference related to CYP2C9*2 . Values for metabolite formation clearance via metabolites M1 and M5 were 1.4, 1.7, 1.4, 1.0, 0.77, and 0.18 L/h in carriers of genotypes *1/*1 , *1/*2 , *2/*2 , *1/*3 , *2/*3 , and *3/*3 , respectively (P < .001). From 0 to 8 hours after torsemide administration, Na + , K + , and Cl - elimination was higher in carriers of CYP2C9*3 alleles than in carriers of the homozygous wild-type genotype, and 24-hour uric acid elimination values in urine were 451, 350, and 249 mg in carriers of 0, 1, and 2 CYP2C9*3 alleles, respectively (P = .003). CONCLUSION: Torsemide pharmacokinetics differed significantly between subgroups with different CYP2C9 genotypes, and diuretic effects were slightly more exaggerated in carriers of CYP2C9*3 alleles. To answer the question of whether these findings have clinical implications, further studies in patients undergoing long-term torsemide treatment are required.

Pharmacogenomics of diuretic drugs: data on rare monogenic disorders and on polymorphisms and requirements for further research.

This review summarizes the current status of our knowledge about the role of pharmacogenetic variation in response to diuretics and suggests future research topics for the field. Genes with a role in the pharmacokinetics of most diuretics are renal drug transporters, especially OAT1, OAT3 and OCT2 (genes SLC22A6, SLC22A8 and SLC22A2) whereas variants in carbonic anhydrase (CA), cytochrome P450 enzymes and sulfotransferases are relevant only for specific substances. Genes on the pharmacodynamic side include the primary targets of thiazide, loop, K(+)-sparing and aldosterone antagonistic diuretics: NCC, NKCC2, ENaC and the mineralocorticoid receptor (genes SLC12A3, SLC12A1, SCNN1A, B, G and NR3C2). Rare variants of these proteins cause Gitelman's syndrome, Bartter's syndrome, Liddle's syndrome or pregnancy-induced hypertension. Polymorphisms in these and in associated proteins such as GNB3, alpha-adducin and angiotensin-converting enzyme (ACE) seem to be clinically relevant. In conclusion, first knowledge has evolved that efficacy of diuretic drugs may be determined by genetic polymorphisms in genes determining pharmacokinetics and pharmacodynamics of this drug class. In the future, the selection of a diuretic drug or the dosing schedules may be individually chosen based on pharmacogenetic parameters, however, many questions remain to be answered before this fantasy becomes reality.

Educating orally anticoagulated patients in drug safety: a cluster-randomized study in general practice.

BACKGROUND: Orally anticoagulated patients with insufficient knowledge about their treatment have a higher risk of complications. Standardized patient education could raise their level of knowledge and improve time spent within target INR range. METHODS: This cluster randomized trial included 319 anticoagulated patients drawn from 22 general medical practices. 185 patients received patient education, conducted by practice nurses, consisting of a video, a brochure, and a questionnaire; 134 control patients received only the brochure. The primary endpoint was knowledge about treatment six months after the patient education session. The secondary endpoints were time in the INR (international normalized ratio) target range and complications of anticoagulation. RESULTS: Patients in the intervention and control groups were of comparable mean age (73 vs. 72 years). They answered a comparable number of questions correctly before the intervention (6.8 ± 0.2 vs. 6.7 ± 0.2) but differed significantly on this measure at six months (9.9 ± 0.2 vs. 7.6 ± 0.2, mean difference 2.3 questions, 95% confidence interval [CI] 1.5-3.1, p< 0.001). In the six months prior to the intervention, the INR was in the target range 65 ± 2% vs. 66 ± 3% of the time; in the six months afterward, 71 ± 1% vs. 64 ± 3% of the time (mean difference 7 percentage points, 95% CI -2 to -16 percentage points, p = 0.11). The complication rates were comparable in the two groups (12% vs. 16%, p = 0.30). Patients in the intervention group approved of patient education sessions to a greater extent than control patients (87% vs. 56%). CONCLUSION: Patient education was found to be practical, to improve knowledge relating to patient safety in a durable manner, and to meet with the approval of the patients who received it. There was a statistically non-significant trend toward an improvement of the time spent in the INR target range. In view of the major knowledge deficits of orally anticoagulated patients, standardized patient education ought to be made a part of their routine care.

Amelogenin-based sex identification as a strategy to control the identity of DNA samples in genetic association studies.

Misassignment between DNA samples and clinical or epidemiological data may compromise the results of genetic association studies. Genotyping in replicates or controlling for Hardy-Weinberg equilibrium cannot identify misassignments caused by sample mix-ups. DNA-based sex identification (sex typing) is currently the best strategy to identify mix-ups. Here we review the available methods and present validated protocols for sex typing. The protocols are based on single-nucleotide differences between the human amelogenin genes, AMELX and AMELY, and are optimized for real-time PCR (TaqMan), primer-extension (SNaPshot) and PCR-RFLP genotyping platforms. In addition, we review the limitations of the sex-typing strategy, including a limited ability to identify single sample mix-ups, the dependence of the power of this approach on the sex distribution in the study population, and rare genetic conditions. Alternative strategies for mix-up identification and possible consequences of mix-up identification are also discussed.

Implementing the cross-disciplinary subject of palliative medicine (Q13) against the backdrop of recent changes of the legal framework using University Medical School Göttingen as an example.

Palliative care for patients with advanced and progressive diseases has recently become an integrated and compulsory part of undergraduate training in Germany. Up until now, undergraduate teaching in this cross-disciplinary medical field varied and therefore problems during the implementation process with regard to formal aspects and teaching content are to be expected. This contribution summarizes the new legislative framework for palliative care as an independent specialty in undergraduate medical training and describes format, content and problems of the current implementation process at the University Medical School Göttingen, in order to provide advice and support for other faculties.

Hydrochlorothiazide efficacy and polymorphisms in ACE, ADD1 and GNB3 in healthy, male volunteers.

OBJECTIVE: The antihypertensive effect of thiazide diuretics has recently been associated with genetic variation in the angiotensin I-converting enzyme (ACE), alpha-adducin (ADD1) and the G protein subunit beta3 (GNB3). Analysis of short-term diuretic effects may provide insight into the mechanisms behind these findings. METHODS: A total of 103 male volunteers took 25 and 100 mg hydrochlorothiazide (HCT) after a placebo day, each. We measured volume, sodium, chloride, potassium, calcium excretion, blood pressure and heart rate. RESULTS: Excretion and cardiovascular parameters were highly constant between the 2 placebo days. The resting heart rate was 2-3 beats/minute (bpm) higher per ACE insertion allele on all 4 study days. The HCT-induced excretion of sodium, chloride and volume was independent of the genotypes. The additional potassium excretion induced by 100 mg HCT was 44+/-21, 33+/-27 and 16+/-26 mmol (mean+/-SD, p<0.001) in ACE II, ID and DD carriers and the same trend was observed after 25 mg HCT. As a second finding, the 100 mg HCT-induced calcium retention was 0.2+/-1.2, 0.7+/-0.8 and 1.7+/-2.1 mmol in ADD1 Gly/Gly, Gly/Trp and Trp/Trp carriers (p=0.002) and the same trend existed after 25 mg HCT. CONCLUSION: The effects of genetic polymorphisms were stronger with the higher diuretic dose. ACE insertion allele carriers appeared to be more prone to hypokalaemia than deletion allele carriers. ADD1 Trp460 carriers may especially benefit from the calcium-sparing effect of thiazides. Both associations should be further studied in long-term treatment with thiazide diuretics.