A real-world study of cardiac events in > 3700 patients with HER2-positive early breast cancer treated with trastuzumab: final analysis of the OHERA study.

PURPOSE: Cardiac dysfunction risk associated with intravenous trastuzumab (H IV) treatment may differ in real-world practice versus randomized trials. We investigated cardiac events in patients with HER2-positive early breast cancer (EBC) treated with H IV as adjuvant therapy in routine practice. METHODS: The observational study of cardiac events in patients with HER2-positive EBC treated with Herceptin (OHERA; NCT01152606) enrolled patients with stage I-IIIb disease eligible for H IV in the adjuvant setting per the European Summary of Product Characteristics (SmPC). Primary outcomes were symptomatic congestive heart failure incidence (CHF; New York Heart Association class II-IV) and cardiac death. Patient visits/assessments were per local practice. RESULTS: 3733 Patients received ≥ 1 H IV dose per local practice; 88.9% received H IV for > 300 days (median follow-up: ~ 5 years). Prior to disease recurrence (if any), symptomatic CHF occurred in 106 patients (2.8%); 6 (0.2%) cardiac deaths occurred (5 in patients with cardiac disease history). Median time to symptomatic CHF onset was 5.7 months (95% CI 5.3-6.5); 77/106 (72.6%) patients with symptomatic CHF achieved resolution. CHF incidence was higher in patients ≥ 65 years, and those with pre-existing cardiac conditions, hypertension, or left ventricular ejection fraction ≤ 55% at baseline. CONCLUSIONS: OHERA is the largest prospective observational study to investigate the cardiac safety of H IV as adjuvant EBC therapy in a real-world setting. Symptomatic CHF and cardiac event incidences were consistent with randomized trials in this setting and baseline risk factors identified in the H IV European SmPC.

Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study.

Background: The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods: Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results: In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Conclusion: Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration: ClinicalTrials.gov NCT02075840.

Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) reduce the need for red blood cell transfusions; however, they increase the risk of thromboembolic events and mortality. The impact of ESAs on quality of life (QoL) is controversial and led to different recommendations of medical societies and authorities in the USA and Europe. We aimed to critically evaluate and quantify the effects of ESAs on QoL in cancer patients. METHODS: We included data from randomised controlled trials (RCTs) on the effects of ESAs on QoL in cancer patients. Randomised controlled trials were identified by searching electronic data bases and other sources up to January 2011. To reduce publication and outcome reporting biases, we included unreported results from clinical study reports. We conducted meta-analyses on fatigue- and anaemia-related symptoms measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) and FACT-Anaemia (FACT-An) subscales (primary outcomes) or other validated instruments. RESULTS: We identified 58 eligible RCTs. Clinical study reports were available for 27% (4 out of 15) of the investigator-initiated trials and 95% (41 out of 43) of the industry-initiated trials. We excluded 21 RTCs as we could not use their QoL data for meta-analyses, either because of incomplete reporting (17 RCTs) or because of premature closure of the trial (4 RCTs). We included 37 RCTs with 10581 patients; 21 RCTs were placebo controlled. Chemotherapy was given in 27 of the 37 RCTs. The median baseline haemoglobin (Hb) level was 10.1 g dl(-1); in 8 studies ESAs were stopped at Hb levels below 13 g dl(-1) and in 27 above 13 g dl(-1). For FACT-F, the mean difference (MD) was 2.41 (95% confidence interval (95% CI) 1.39-3.43; P<0.0001; 23 studies, n=6108) in all cancer patients and 2.81 (95% CI 1.73-3.90; P<0.0001; 19 RCTs, n=4697) in patients receiving chemotherapy, which was below the threshold (≥ 3) for a clinically important difference (CID). Erythropoiesis-stimulating agents had a positive effect on anaemia-related symptoms (MD 4.09; 95% CI 2.37-5.80; P=0.001; 14 studies, n=2765) in all cancer patients and 4.50 (95% CI 2.55-6.45; P<0.0001; 11 RCTs, n=2436) in patients receiving chemotherapy, which was above the threshold (≥ 4) for a CID. Of note, this effect persisted when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy. There was some evidence that the MDs for FACT-F were above the threshold for a CID in RCTs including cancer patients receiving chemotherapy with Hb levels below 12 g dl(-1) at baseline and in RCTs stopping ESAs at Hb levels above 13 g dl(-1). However, these findings for FACT-F were not confirmed when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy. CONCLUSIONS: In cancer patients, particularly those receiving chemotherapy, we found that ESAs provide a small but clinically important improvement in anaemia-related symptoms (FACT-An). For fatigue-related symptoms (FACT-F), the overall effect did not reach the threshold for a CID.

Integrating fragmented evidence by network meta-analysis: relative effectiveness of psychological interventions for adults with post-traumatic stress disorder.

BACKGROUND: To summarize the available evidence on the effectiveness of psychological interventions for patients with post-traumatic stress disorder (PTSD). METHOD: We searched bibliographic databases and reference lists of relevant systematic reviews and meta-analyses for randomized controlled trials that compared specific psychological interventions for adults with PTSD symptoms either head-to-head or against control interventions using non-specific intervention components, or against wait-list control. Two investigators independently extracted the data and assessed trial characteristics. RESULTS: The analyses included 4190 patients in 66 trials. An initial network meta-analysis showed large effect sizes (ESs) for all specific psychological interventions (ESs between -1.10 and -1.37) and moderate effects of psychological interventions that were used to control for non-specific intervention effects (ESs -0.58 and -0.62). ES differences between various types of specific psychological interventions were absent to small (ES differences between 0.00 and 0.27). Considerable between-trial heterogeneity occurred (τ²= 0.30). Stratified analyses revealed that trials that adhered to DSM-III/IV criteria for PTSD were associated with larger ESs. However, considerable heterogeneity remained. Heterogeneity was reduced in trials with adequate concealment of allocation and in large-sized trials. We found evidence for small-study bias. CONCLUSIONS: Our findings show that patients with a formal diagnosis of PTSD and those with subclinical PTSD symptoms benefit from different psychological interventions. We did not identify any intervention that was consistently superior to other specific psychological interventions. However, the robustness of evidence varies considerably between different psychological interventions for PTSD, with most robust evidence for cognitive behavioral and exposure therapies.

Prevalence of cam and pincer-type deformities on hip MRI in an asymptomatic young Swiss female population: a cross-sectional study.

OBJECTIVES: Femoroacetabular impingement is proposed to cause early osteoarthritis (OA) in the non-dysplastic hip. We previously reported on the prevalence of femoral deformities in a young asymptomatic male population. The aim of this study was to determine the prevalence of both femoral and acetabular types of impingement in young females. METHODS: We conducted a population-based cross-sectional study of asymptomatic young females. All participants completed a set of questionnaires and underwent clinical examination of the hip. A random sample was subsequently invited to obtain magnetic resonance images (MRI) of the hip. All MRIs were read for cam-type deformities, increased acetabular depths, labral lesions, and impingement pits. Prevalence estimates of cam-type deformities and increased acetabular depths were estimated, and relationships between deformities and signs of joint damage were examined using logistic regression models. RESULTS: The study included 283 subjects, and 80 asymptomatic females with a mean age of 19.3 years attended MRI. Fifteen showed some evidence of cam-type deformities, but none were scored to be definite. The overall prevalence was therefore 0% [95% confidence interval (95% CI) 0-5%]. The prevalence of increased acetabular depth was 10% (95% CI 5-19). No association was found between increased acetabular depth and decreased internal rotation of the hip. Increased acetabular depth was not associated with signs of labral damage. CONCLUSIONS: Definite cam-type deformities in women are rare compared to men, whereas the prevalence of increased acetabular depth is higher, suggesting that femoroacetabular impingement has different gender-related biomechanical mechanisms.

Treatment failure in pneumonia: impact of antibiotic treatment and cost analysis.

The aim of this study was to investigate treatment failure (TF) in hospitalised community-acquired pneumonia (CAP) patients with regard to initial antibiotic treatment and economic impact. CAP patients were included in two open, prospective multicentre studies assessing the direct costs for in-patient treatment. Patients received treatment either with moxifloxacin (MFX) or a nonstandardised antibiotic therapy. Any change in antibiotic therapy after >72 h of treatment to a broadened antibiotic spectrum was considered as TF. Overall, 1,236 patients (mean ± SD age 69.6 ± 16.8 yrs, 691 (55.9%) male) were included. TF occurred in 197 (15.9%) subjects and led to longer hospital stay (15.4 ± 7.3 days versus 9.8 ± 4.2 days; p < 0.001) and increased median treatment costs (€2,206 versus €1,284; p<0.001). 596 (48.2%) patients received MFX and witnessed less TF (10.9% versus 20.6%; p < 0.001). After controlling for confounders in multivariate analysis, adjusted risk of TF was clearly reduced in MFX as compared with ß-lactam monotherapy (adjusted OR for MFX 0.43, 95% CI 0.27-0.68) and was more comparable with a ß-lactam plus macrolide combination (BLM) (OR 0.68, 95% CI 0.38-1.21). In hospitalised CAP, TF is frequent and leads to prolonged hospital stay and increased treatment costs. Initial treatment with MFX or BLM is a possible strategy to prevent TF, and may thus reduce treatment costs.

An examination chair to measure internal rotation of the hip in routine settings: a validation study.

OBJECTIVE: To determine the performance of a newly developed examination chair as compared with the clinical standard of assessing internal rotation (IR) of the flexed hip with a goniometer. METHODS: The examination chair allowed measurement of IR in a sitting position simultaneously in both hips, with hips and knees flexed 90 degrees, lower legs hanging unsupported and a standardized load of 5 kg applied to both ankles using a bilateral pulley system. Clinical assessment of IR was performed in supine position with hips and knees flexed 90 degrees using a goniometer. Within the framework of a population-based inception cohort study, we calculated inter-observer agreement in two samples of 84 and 64 consecutive, unselected young asymptomatic males using intra-class correlation coefficients (ICC) and determined the correlation between IR assessed with examination chair and clinical assessment. RESULTS: Inter-observer agreement was excellent for the examination chair (ICC right hip, 0.92, 95% confidence interval [CI] 0.89-0.95; ICC left hip, 0.90, 95% CI 0.86-0.94), and considerably higher than that seen with clinical assessment (ICC right hip, 0.65, 95% CI 0.49-0.77; ICC left hip, 0.69, 95% CI 0.54-0.80, P for difference in ICC between examination chair and clinical assessment

A randomised controlled trial of spinal manipulative therapy in acute low back pain.

OBJECTIVE: To determine whether treatment with spinal manipulative therapy (SMT) administered in addition to standard care is associated with clinically relevant early reductions in pain and analgesic consumption. METHODS: 104 patients with acute low back pain were randomly assigned to SMT in addition to standard care (n = 52) or standard care alone (n = 52). Standard care consisted of general advice and paracetamol, diclofenac or dihydrocodeine as required. Other analgesic drugs or non-pharmacological treatments were not allowed. Primary outcomes were pain intensity assessed on the 11-point box scale (BS-11) and analgesic use based on diclofenac equivalence doses during days 1-14. An extended follow-up was performed at 6 months. RESULTS: Pain reductions were similar in experimental and control groups, with the lower limit of the 95% CI excluding a relevant benefit of SMT (difference 0.5 on the BS-11, 95% CI -0.2 to 1.2, p = 0.13). Analgesic consumptions were also similar (difference -18 mg diclofenac equivalents, 95% CI -43 mg to 7 mg, p = 0.17), with small initial differences diminishing over time. There were no differences between groups in any of the secondary outcomes and stratified analyses provided no evidence for potential benefits of SMT in specific patient groups. The extended follow-up showed similar patterns. CONCLUSIONS: SMT is unlikely to result in relevant early pain reduction in patients with acute low back pain.

Exploratory analysis of population pharmacokinetic data from clinical trials with application to isradipine.

Drug level monitoring during routine clinical visits in the course of phase III trials provides a means to document pharmacokinetic variability in a patient population. Such a pharmacokinetic screen was performed for the new calcium antagonist isradipine. A total of 697 blood samples were collected at any time after the morning dose from 252 patients who had received oral doses of isradipine. Three approaches of data analysis based on exploratory (graphical and statistical) techniques were used to relate plasma level to patient demographic data and laboratory parameters. The pharamacokinetics of isradipine seemed to be influenced by the demographic variables of age (already detected in conventional studies) and weight, as well as by the blood serum levels of inorganic phosphorous, uric acid, alkaline phosphatase, and bilirubin, but only to a small, clinically irrelevant extent. The findings from the three approaches were complementary. They suggest that a pharmacokinetic screening in clinical trials is feasible at reasonable experimental cost and effort and provides useful data on interindividual and intraindividual pharmacokinetic variability in patients.

Analgesic effect of fluproquazone in postoperative patients.

In 4 double-blind, randomized, stratified, parallel group studies, single oral doses of fluproquazone (75 to 200 mg), a new nonsteroidal anti-inflammatory analgesic, were compared with aspirin (1,000 mg) and placebo in a total of 672 hospitalized patients with moderate or severe pain following episiotomy or other surgical interventions. A dose-dependent effect of fluproquazone which was highly significantly superior to placebo and which resembled the effect of aspirin with respect to onset, degree, and duration was noted in all studies. Fluproquazone, 100 to 150 mg, was found to be approximately equiactive to 1,000 mg of aspirin and better tolerated.

Headache as a model for assessing mild analgesic drugs.

A method for the evaluation of the efficacy of mild analgesic drugs in outpatients with nonmigrainous headache is described. During the 3-hour drug evaluation period, patients were required to record at hourly intervals their pain intensity using both a verbal rating and a visual analog scale, their pain relief, and the occurrance of side effects. The results obtained in six studies consisted of comparisons of reference compounds aspirin (1000 mg) and two analgesic combinations (containing aminophenazone, caffeine, and butalbital); test medications aspirin (500 mg), codeine (30 mg), proquazone (300 mg), and new formulations of the two analgesic combinations (aminophenazone replaced by propyphenazone); and, in every study, placebo. In a seventh study, the analgesic effects of three doses aspirin (250, 500, and 1000 mg) were compared with that of placebo. Every study was conducted under double-blind, complete crossover conditions, and between 24 and 36 patients were used in each study. Using parametric and nonparametric statistical analyses, the reference compounds and the majority of the test medications exhibited significant analgesic properties. Also, a highly significant dose--response effect was demonstrated for aspirin. It is concluded that the headache model is a practicable, reliable, and sensisive method for the evaluation of the effectiveness of mild analgesic drugs.

[Mucus models for investigation of intestinal absorption mechanisms. 3. A mathematical simulation model of drug diffusion through enteral mucus]. / Mucusmodelle zur Untersuchung von intestinalen Absorptionsmechanismen. 3. Mitteilung: Ein mathematisches Simulationsmodell der Wirkstoffdiffusion durch enteralen Mucus.

The diffusion of drug substance in a closed three-compartment model through a mucus layer to equilibrium is simulated by available pharmacokinetic programs. The obtained curves conform very well to the values experimentally found. If mucus is replaced by buffer solution an explicit equation from the literature, the method used and the experimental findings give the same results. Examination of the rate constants k1 for the diffusion in, kD through and k2 from the mucus shows the significance of the relation k1/k2 > 1, = 1, < 1 as a measure for the affinity of the active agent to the mucus. The discussion of the kinetic parameters shows, as in previous results, no criterion for assuming specific mucus binding. Because of its unspecifity the usual term "mucus binding" should be replaced by "mucus retention".

Pharmacokinetics of SMS 201-995 in healthy subjects.

The pharmacokinetics of a new somatostatin derivative, SMS 201-995, was investigated in a group of eight healthy subjects. SMS 201-995 was given intravenously in doses of 25 micrograms, 50 micrograms, 100 micrograms, and 200 micrograms and also subcutaneously in doses of 50 micrograms, 100 micrograms, 200 micrograms, and 400 micrograms in accordance with a randomized Latin-square design. Blood samples were taken up to 8 h. The tolerability of SMS 201-995 was very good. Routine blood chemistry variables remained normal. After intravenous administration of SMS 201-995 initial half-lives ranging from 9 +/- 2 min to 14 +/- 4 min and second half-lives of from 72 +/- 22 min to 98 +/- 37 min were calculated for the different doses. SMS 201-995 was rapidly absorbed after subcutaneous injection with a half-life ranging from 5.3 +/- 2.2 min to 11.7 +/- 7.6 min. The disposition half-life was from 88 +/- 20 min to 102 +/- 16 min for the different doses. Cp(tmax) and AUC (0 - infinity) increased dose-dependently after both routes of administration, pointing to linear pharmacokinetics for SMS 201-995. On the basis of its good tolerability, slow plasma clearance, and long action, SMS 201-995 represents a valuable tool for further clinical studies.

The prevalence of widespread central hypersensitivity in chronic pain patients.

BACKGROUND: Chronic pain is associated with generalized hypersensitivity and impaired endogenous pain modulation (conditioned pain modulation; CPM). Despite extensive research, their prevalence in chronic pain patients is unknown. This study investigated the prevalence and potential determinants of widespread central hypersensitivity and described the distribution of CPM in chronic pain patients. METHODS: We examined 464 consecutive chronic pain patients for generalized hypersensitivity and CPM using pressure algometry at the second toe and cold pressor test. Potential determinants of generalized central hypersensitivity were studied using uni- and multivariate regression analyses. Prevalence of generalized central hypersensitivity was calculated for the 5th, 10th and 25th percentile of normative values for pressure algometry obtained by a previous large study on healthy volunteers. CPM was addressed on a descriptive basis, since normative values are not available. RESULTS: Depending on the percentile of normative values considered, generalized central hypersensitivity affected 17.5-35.3% of patients. 23.7% of patients showed no increase in pressure pain threshold after cold pressor test. Generalized central hypersensitivity was more frequent and CPM less effective in women than in men. Unclearly classifiable pain syndromes showed higher frequencies of generalized central hypersensitivity than other pain syndromes. CONCLUSIONS: Although prevalent in chronic pain, generalized central hypersensitivity is not present in every patient. An individual assessment is therefore required in order to detect altered pain processing. The broad basic knowledge about central hypersensitivity now needs to be translated into concrete clinical consequences, so that patients can be offered an individually tailored mechanism-based treatment.

Extension of the Loo-Riegelman method to pharmacokinetic data at steady state.

The method of Loo and Riegelman is often used to calculate the relative amount absorbed as a function of time from plasma concentration data which follow a two-compartment open model. The method, however, is applicable only to single-dose data, whereas there is sometimes interest in the absorption-time profile at steady state after multiple doses. The method is modified here so that it can be applied to steady-state data and its use with a practical example is illustrated.

Non-migrainous headache for the evaluation of oral analgesics.

1 Eight double-blind, randomized, placebo-controlled, single-dose, cross-over studies were carried out to evaluate the usefulness of testing the acute analgesic effect of drugs in out-patients with non-migrainous headache. 2 The reference compounds were either (1) aspirin, (2) a combination of aminopyrine, caffeine and butalbarbital (Optalidon), and (3) a combination of (2) with dihydroergotamine (Tonopan). 3 The test compounds were (1) proquazone, (2) fluproquazone and (3) and (4), new formulations of Optalidon and Tonopan in which the aminopyrine was replaced by propyphenazone. They were all found to be active. 4 A significant, dose-response relationship was established for aspirin (250, 500 and 1000 mg). 5 It is concluded that the non-migrainous headache model is a practical, reproducible and sensitive method for the investigation of the acute efficacy of analgesics.

Comparative pharmacokinetic investigations with tritium-labeled ergot alkaloids after oral and intravenous administration man.

Pharmacokinetic studies were carried out with nine tritium-labeled ergot alkaloids (dihydroergotmine, dihydroergotoxine, dihydroergostine, dihydroergocornine, dihydroergovaline, dihydroergonine, ergotamine, 1-methyl-ergotamine, and bromocriptine). Each drug was administered to 6 subjects in a randomized cross-over design as single oral and intravenous doses. Plasma levels and urinary excretion of tritium-labeled material were analyzed on a phenomenological basis by non-linear regression as a sum of exponentials. All substances showed the highest plasma concentration about 2 hours after oral administration (range 1.0-2.7 hours). The mean invasion half-life was 0.5 hours (range 0.32-1.12 hours). The mean elimination half-lives ranged from 1.4-6.2 hours for the alpha-phase and from 13 to 50 hours for the beta-phase, the longest values being observed with bromocriptine. From cumulative urinary excretion data after oral and after intravenous administration, a quotient of absorption was calculated. Values between 25 and 30% were found for most dihydrogenated drugs, namely dihydroergotamine, dihydroergotoxine, dihydroergostine, and dihydroergocornine, the only exceptions being dihydroergovaline and dihydroergonine, which were less well absorbed. Ergotamine and 1-methyl-ergotamine had an absorption quotient of about two-thirds and bromocriptine was nearly completely absorbed.

The effect of a new inotropic agent, DPI 201-106, on systolic time intervals and the electrocardiogram in healthy subjects.

1. DPI 201-106 (DPI) is a novel inotropic agent, with Na+ channel agonistic action combined with a sensitization of contractile proteins to Ca++. In a double-blind trial in healthy volunteers (n = 20) cardiovascular effects (blood pressure, heart rate, ECG) of single oral doses were studied. In addition systolic time intervals (STIs) were assessed in 10 of these subjects. DPI plasma concentrations were measured by h.p.l.c. 2. Preejection period was shortened by 14 ms (P less than 0.01) and 30 ms (P less than 0.01) 1 h after 30 and 60 mg, respectively, suggesting a dose-dependent inotropic effect. Heart rate was slightly reduced after both doses. Mean blood pressure remained unchanged. 3. Corrected QT interval duration (QTc) was prolonged by a mean of 7 ms (NS) and 22 ms (P less than 0.001) 1 h after 30 and 60 mg, respectively. PQ and QRS intervals remained unaffected. 4. Peak plasma levels were attained at 1-2 h and the terminal elimination half-life was approximately 15 h. 5. It is concluded that DPI has positive inotropic and negative chronotropic properties which make it potentially useful for the treatment of heart failure.