Long-term safety of tiotropium/olodaterol Respimat® in patients with moderate-to-very severe COPD and renal impairment in the TONADO® studies

Introduction: The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO (R) studies (NCT01431274; NCT01431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies. Methods: These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat (R)) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min). Adverse events (AEs) were pooled from both studies. Results: Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment. Conclusion: Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment

Differing severities of acute exacerbations of idiopathic pulmonary fibrosis (IPF): Insights from the INPULSIS\uae trials

Background: Given the broad definition of an acute exacerbation of IPF, it is likely that acute exacerbations are heterogeneous in their aetiology, severity and clinical course. We used pooled data from the INPULSIS\uae trials of nintedanib versus placebo to investigate whether acute exacerbations reported as serious adverse events were associated with higher mortality than those reported as non-serious adverse events and to assess the effect of nintedanib on these types of events. Methods: Adverse events considered by an investigator to be an acute exacerbation were adjudicated as a confirmed acute exacerbation, suspected acute exacerbation, or not an acute exacerbation. Time to first investigator-reported acute exacerbation or confirmed/suspected acute exacerbation reported as a serious adverse event or non-serious adverse event over the 52-week treatment period was assessed post-hoc. Deaths were assessed based on data collected over the 52-week treatment period. Results: Of 63 patients who had 651 investigator-reported acute exacerbation, 48 (76.2%) had a first acute exacerbation reported as a serious adverse event. Thirty-six (3.4%) patients had 651 confirmed/suspected acute exacerbation, of whom 31 had a first event reported as a serious adverse event. Investigator-reported acute exacerbations reported as serious adverse events occurred in 23 patients in the nintedanib group and 26 in the placebo group. Confirmed/suspected acute exacerbations reported as serious adverse events occurred in 10 and 21 patients in these groups, respectively. Nintedanib significantly reduced the risk of a first acute exacerbation reported as a serious adverse event (HR 0.57 [95% CI: 0.32, 0.99]; p = 0.0476) and the risk of a first confirmed/suspected acute exacerbation reported as a serious adverse event (HR 0.30 [95% CI: 0.14, 0.64]; p = 0.0019) versus placebo. A higher proportion of patients with investigator-reported acute exacerbations reported as serious adverse events died than patients with acute exacerbations reported as non-serious adverse events (61.2% versus 7.1%). Conclusion: Different severities of acute exacerbation of IPF may exist. Acute exacerbations reported as serious adverse events in the INPULSIS\uae trials were associated with high mortality. Nintedanib significantly reduced the risk of acute exacerbations reported as serious adverse events. Trial registration: ClinicalTrials.gov NCT01335464 and NCT01335477

Recruiting Hard-to-Reach Subjects for Exercise Interventions: A Multi-Centre and Multi-Stage Approach Targeting General Practitioners and Their Community-Dwelling and Mobility-Limited Patients

The general practitioner (GP)’s practice appears to be an ideal venue for recruiting community-dwelling older adults with limited mobility. This study (Current Controlled Trials ISRCTN17727272) aimed at evaluating the recruiting process used for a multi-centre exercise intervention (HOMEfit). Each of six steps resulted in an absolute number of patients (N1–N6). Sex and age (for N4–N6) and reasons for dropping out were assessed. Patient database screening (N1–N3) at 15 GP practices yielded N1 = 5,990 patients aged 70 and above who had visited their GP within the past 6 months, N2 = 5,467 after exclusion of institutionalised patients, N3 = 1,545 patients eligible. Using a pre-defined limitation algorithm in order to conserve the practices’ resources resulted in N4 = 1,214 patients (80.3 ± 5.6 years, 68% female), who were then officially invited to the final assessment of eligibility at the GP’s practice. N5 = 434 patients (79.5 ± 5.4 years, 69% female) attended the practice screening (n = 13 of whom had not received an official invitation). Finally, N6 = 209 (79.8 ± 5.2 years, 74% female) were randomised after they were judged eligible and had given their written informed consent to participate in the randomised controlled trial (overall recruitment rate: 4.4%). The general strategy of utilising a GP’s practice to recruit the target group proved beneficial. The data and experiences presented here can help planners of future exercise-intervention studies

Evidenz und Tradition am Beispiel der Phytopharmaka

Summary Herbal medicinal products - Evidence and tradition from a historical perspective Background: Aside from the fully licensed herbal medicines there are products on the European pharmaceutical market which are registered by virtue of their longstanding traditional use. The normal registration procedure does not apply to them because presently they do not meet the legal requirements for a full license as set out in the relevant European Union Directive. One of these requirements, proof of tradition, has so far been dealt with in different ways and fails to meet the criteria of good practice. Method: This analysis is based on a selective literature search in PubMed and in databases of medical and pharmaceutical history, interviews with licensing experts, a consensus meeting attended by researchers with a background in general medicine, phytotherapy, medical and pharmaceutical history, biometry, ethnopharmacology, pharmacognosy and the pharmaceutical industry. Results and discussion: The 2004 EU Directive, which governs the registration of Traditional Herbal Medicinal Products and demands proof of tradition, is a regulatory construct and, above all, the outcome of a political process that has ended in a pragmatic compromise. The concept of tradition applied in the Directive does not sufficiently reflect the semantic breadth of the term. The only condition defined is that a specific commercial preparation needs to have been on the market for 30 years (15 of them inside the EU). Such an approach does not make full scientific use of the evidence available because the information excerpted from historical sources, if adequately processed, may yield valuable insights. This applies to indications, modes of application, efficacy and product safety (innocuousness). Such criteria should enter in full into the benefit-risk-analysis of applied preparations, in the registration process as well as in the therapeutic practice. Conclusion: When registering Traditional Herbal Medicinal Products the criterion of evidence-based medicine will only be met if all the facts available are assessed and evaluated, over and above the formally stipulated regulatory provisions (30 years, product reference). To this end, the scientific methods (from among the natural, life or cultural sciences), which are recognized as authoritative in each case, must be applied

Hospital-based, prospective, multicentre surveillance to determine the incidence of intussusception in children aged below 15 years in Germany

<p>Abstract</p> <p>Background</p> <p>A new vaccine against Rotavirus (RV) gastroenteritis was introduced in Germany in 2006. In 1997 the first RV vaccine was withdrawn due to an increased incidence in intussusception (IS). Thus, an accurate estimation of the incidence of IS is important for post-licensure surveillance.</p> <p>Methods</p> <p>IS-Data were obtained from the 'Erhebungseinheit für seltene pädiatrische Erkrankungen Deutschland' (ESPED, German surveillance unit for rare pediatric diseases) collaborations' central register where all cases of intussusception in Germany for the years 2006 and 2007 are collected (n = 1200). In order to obtain an unbiased estimate of the incidence, it is necessary to determine the population under risk out of which these cases originated, and the proportion of real cases not reported to the registry (underreporting). In order to assess underreporting, a random sample of 31 hospitals was re-assessed by an outside reviewer. The estimation of incidence was done using a single Maximum-Likelihood (ML) estimator based on data from both the registry and the sample.</p> <p>Results</p> <p>The uncorrected observed incidence was calculated to be 26.6/100,000 child-years for children below 1 year old, 23.8 for those below 2 years old, and 5.2 for those below 15 years old. The review revealed a mean reporting quota of about 41% and the ML approach yielded an incidence of 51.5/100,000 child-years (95%CI [41.7;61.1]) for children below 2 years of age.</p> <p>Conclusions</p> <p>While substantial under-reporting led to very conservative estimates of the IS incidence, the approach described here allows an accurate estimation of IS incidence including corresponding confidence bands. Therefore, ML estimation is a straightforward instrument to derive stable, unbiased estimates in epidemiological studies with incomplete data.</p

Randomised controlled comparison of the Health Survey Short Form (SF-12) and the Graded Chronic Pain Scale (GCPS) in telephone interviews versus self-administered questionnaires. Are the results equivalent?

<p>Abstract</p> <p>Background</p> <p>The most commonly used survey methods are self-administered questionnaires, telephone interviews, and a mixture of both. But until now evidence out of randomised controlled trials as to whether patient responses differ depending on the survey mode is lacking. Therefore this study assessed whether patient responses to surveys depend on the mode of survey administration. The comparison was between mailed, self-administered questionnaires and telephone interviews.</p> <p>Methods</p> <p>A four-armed, randomised controlled two-period change-over design. Each patient responded to the same survey twice, once in written form and once by telephone interview, separated by at least a fortnight. The study was conducted in 2003/2004 in Germany. 1087 patients taking part in the German Acupuncture Trials (GERAC cohort study), who agreed to participate in a survey after completing acupuncture treatment from an acupuncture-certified family physician for headache, were randomised. Of these, 823 (664 women) from the ages of 18 to 83 (mean 51.7) completed both parts of the study. The main outcome measure was the comparison of the scores on the 12-Item Short-Form Health Survey (SF-12) and the Graded Chronic Pain Scale (GCPS) questionnaire for the two survey modes.</p> <p>Results</p> <p>Computer-aided telephone interviews (CATI) resulted in significantly fewer missing data (0.5%) than did mailed questionnaires (2.8%; p < 0.001). The analysis of equivalence revealed a difference between the survey modes only for the SF-12 mental scales. On average, reported mental status score was 3.5 score points (2.9 to 4.0) lower on the self-administered questionnaire compared to the telephone interview. The order of administration affected results. Patients who responded to the telephone interview first reported better mental health in the subsequent paper questionnaire (mean difference 2.8 score points) compared to those who responded to the paper questionnaire first (mean difference 4.1 score points).</p> <p>Conclusion</p> <p>Despite the comparatively high cost of telephone interviews, they offer clear advantages over mailed self-administered questionnaires as regards completeness of data. Only items concerning mental status were dependent on the survey mode and sequence of administration. Items on physical status were not affected. Normative data for standardized telephone questionnaires could contribute to a better comparability with the results of the corresponding standardized paper questionnaires.</p

General practitioner advice on physical activity: Analyses in a cohort of older primary health care patients (getABI)

<p>Abstract</p> <p>Background</p> <p>Although the benefits of physical activity for health and functioning are recognized to extend throughout life, the physical activity level of most older people is insufficient with respect to current guidelines. The primary health care setting may offer an opportunity to influence and to support older people to become physically active on a regular basis. Currently, there is a lack of data concerning general practitioner (GP) advice on physical activity in Germany. Therefore, the aim of this study was to evaluate the rate and characteristics of older patients receiving advice on physical activity from their GP.</p> <p>Methods</p> <p>This is a cross-sectional study using data collected at 7 years of follow-up of a prospective cohort study (German epidemiological trial on ankle brachial index, getABI). 6,880 unselected patients aged 65 years and above in the primary health care setting in Germany were followed up since October 2001. During the 7-year follow-up telephone interview, 1,937 patients were asked whether their GP had advised them to get regular physical activity within the preceding 12 months. The interview also included questions on socio-demographic and lifestyle variables, medical conditions, and physical activity. Logistic regression analysis (unadjusted and adjusted for all covariables) was used to examine factors associated with receiving advice. Analyses comprised only complete cases with regard to the analysed variables. Results are expressed as odds ratios (ORs) with 95% confidence intervals (95% CI).</p> <p>Results</p> <p>Of the 1,627 analysed patients (median age 77; range 72-93 years; 52.5% women), 534 (32.8%) stated that they had been advised to get regular physical activity. In the adjusted model, those more likely to receive GP advice on physical activity were men (OR [95% CI] 1.34 [1.06-1.70]), patients suffering from pain (1.43 [1.13-1.81]), coronary heart disease and/or myocardial infarction (1.56 [1.21-2.01]), diabetes mellitus (1.79 [1.39-2.30]) or arthritis (1.37 [1.08-1.73]), and patients taking a high (> 5) number of medications (1.41 [1.11-1.80]).</p> <p>Conclusions</p> <p>The study revealed a relatively low rate of older primary health care patients receiving GP advice on physical activity. GPs appeared to focus their advice on patients with chronic medical conditions. However, there are likely to be many more patients who would benefit from advice.</p

The effect of time-to-surgery on outcome in elderly patients with proximal femoral fractures

<p>Abstract</p> <p>Background</p> <p>Whether reducing time-to-surgery for elderly patients suffering from hip fracture results in better outcomes remains subject to controversial debates.</p> <p>Methods</p> <p>As part of a prospective observational study conducted between January 2002 and September 2003 on hip-fracture patients from 268 acute-care hospitals all over Germany, we investigated the relationship of time-to-surgery with frequency of post-operative complications and one-year mortality in elderly patients (age ≥65) with isolated proximal femoral fracture (femoral neck fracture or pertrochanteric femoral fracture). Patients with short (≤12 h), medium (> 12 h to ≤36 h) and long (> 36 h) times-to-surgery, counting from the time of the fracture event, were compared for patient characteristics, operative procedures, post-operative complications and one-year mortality.</p> <p>Results</p> <p>Hospital data were available for 2916 hip-fracture patients (mean age (SD) in years: 82.1 (7.4), median age: 82; 79.7% women). Comparison of groups with short (n = 802), medium (n = 1191) and long (n = 923) time-to-surgery revealed statistically significant differences in a few patient characteristics (age, American Society of Anesthesiologists ratings classification and type of admission) and in operative procedures (total hip endoprosthesis, hemi-endoprosthetic implants, other osteosynthetic procedures). However, comparison of these same groups for frequency of postoperative complications revealed only some non-significant associations with certain complications such as post-operative bleeding requiring treatment (early surgery patients) and urinary tract infections (delayed surgery patients). Both unadjusted rates of one-year all-cause mortality (between 18.1% and 20.5%), and the multivariate-adjusted hazard ratios (HR for time-to-surgery: 1.04; p = 0.55) showed no association between mortality and time-to-surgery.</p> <p>Conclusion</p> <p>Although this study found a trend toward more frequent post-operative complications in the longest time-to-surgery group, there was no effect of time-to-surgery on mortality. Shorter time-to-surgery may be associated with somewhat lower rates of post-operative complications such as decubitus ulcers, urinary tract infections, thromboses, pneumonia and cardiovascular events, and with somewhat higher rates of others such as post-operative bleeding or implant complications.</p