Unmeasured baseline information in left-truncated data situations frequently occurs in observational time-to-event analyses. For instance, a typical timescale in trials of antidiabetic treatment is "time since treatment initiation", but individuals may have initiated treatment before the start of longitudinal data collection. When the focus is on baseline effects, one widespread approach is to fit a Cox proportional hazards model incorporating the measurements at delayed study entry. This has been criticized because of the potential time dependency of covariates. We tackle this problem by using a Bayesian joint model that combines a mixed-effects model for the longitudinal trajectory with a proportional hazards model for the event of interest incorporating the baseline covariate, possibly unmeasured in the presence of left truncation. The novelty is that our procedure is not used to account for non-continuously monitored longitudinal covariates in right-censored time-to-event studies, but to utilize these trajectories to make inferences about missing baseline measurements in left-truncated data. Simulating times-to-event depending on baseline covariates we also compared our proposal to a simpler two-stage approach which performed favorably. Our approach is illustrated by investigating the impact of baseline blood glucose levels on antidiabetic treatment failure using data from a German diabetes register.

OBJECTIVE:Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI.METHODS:In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients.RESULTS:When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint).CONCLUSIONS:Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies.KEY MESSAGES:In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.

In the Titration and Optimization study (TOP-1), addition of insulin glargine to an insufficient therapy with OADs has been examined.• While a number of titration schemes for basal insulin exist, little is known about the actual titration behavior in daily clinical practice.• This sub-analysis was performed to explore real world titration schemes in clinical practice in Germany and how different titration affects efficacy and safety.

Objective: Diabetes mellitus, primarily a metabolic disorder, must be considered also as a vascular disease. Early vascular changes are characterized by hyperperfusion (e.g. eye), vascular remodeling of small arteries and increased pulse wave reflection leading to increased (central) aortic pressure. We investigated the effects of the SGLT-2 inhibitor dapagliflozin on parameters of early micro- and macrovascular changes in patients with type-2 diabetes. Design and method: In this prospective, double-blind, placebo-controlled, cross-over trial 59 patients (61 ± 7.6 years) with type-2 diabetes were randomly assigned to dapagliflozin 10 mg and placebo for 6 weeks. Retinal microvascular structure (wall-to-lumen ratio [WLR]) and retinal capillary flow [RCF]) were non-invasively assessed by scanning laser Doppler flowmetry. In addition, macrovascular parameters (central pulse pressure) were assessed by pulse wave analysis in addition to 24-h ambulatory blood pressure (ABP). Results: Treatment with dapagliflozin for 6 weeks improved diabetic control (HbA1c, fasting and postprandial blood glucose, all p < 0.001) compared to placebo. Compared to placebo treatment with dapagliflozin reduced numerically but not significantly both microvascular parameters (RCF and WLR). When compared to baseline, treatment with dapagliflozin reduced RCF (308 ± 78 vs. 324 ± 84 AU, p = 0.028), indicative of a normalization of retinal hyperperfusion, and prevented vascular remodelling of retinal, which occurred in the placebo group (WLR: 0.356 ± 0.1 vs. 0.391 ± 0.1, p = 0.034). Moreover, compared to placebo, treatment of dapagliflozin reduced systolic and diastolic 24-h ABP (126 ± 11/75 ± 8 vs. 129 ± 12/77 ± 7 mmHg, p = 0.021/0.027), and central pulse pressure (40.9 ± 11 vs. 43.9 ± 12 mmHg, p = 0.05). Conclusions: Overall, our data indicate that treatment with the SGLT-2 inhibitor dapagliflozin exerts beneficial effects on vascular parameters of the micro- and macrocirculation, suggesting an improvement of cardiovascular prognosis.

Einleitung: Als lean diabetes wird eine Diabetesform von Menschen mit Typ 2 Diabetes und niedrigem bis niedrig normalem Body Mass Index (BMI; kg/m2) bezeichnet. Studien berichten, dass oft Männer betroffen sind, die Behandlung früh mit Insulin erfolgt und sich häufiger Alkoholismus, Nikotinabusus und Pankreatitiden finden. Auch eine erhöhte Gesamtmortalität wurde beschrieben. Wir haben daraufhin Menschen mit lean diabetes in der DiaRegis Kohorte untersucht.

Objective: Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in type-2 diabetes. The exaggerated NO production, compensatory to the increased oxidative stress in diabetes, lead to early hemodynamic changes characterized by hyperfiltration, hyperperfusion and increased vascular permeability. Design and method: In this randomized, double-blind, investigator-initiated trial, 62 patients (57 ± 9.3 years) with type-2 diabetes were randomly assigned to linagliptin 10 mg (n = 30) or placebo (n = 32) for 4 weeks. Endothelial function of the renal vasculature was assessed by constant-infusion input-clearance technique with p-amminohippurate and inulin, as well as urinary albumin creatinine ratio (UACR), both before and after blockade of NOS with NG-monomethyl-L-arginine (L-NMMA). Results: Treatment with linagliptin for 4 weeks tended to reduce fasting (137 ± 26 versus 129 ± 30 mg/ml, p = 0.072), postprandial (171 ± 22 versus 160 ± 45 mg/ml, p = 0.076) blood glucose and HbA1c (6.98 ± 0.7 versus 6.86 ± 0.8 %, p = 0.089), whereas no change occurred with placebo. Renal plasma flow (RPF) and glomerular filtration rate did not change after linagliptin and placebo, without any difference between the groups. After 4 weeks the absolute [percental] change in RPF due to L-NMMA was lower in linagliptin group (-46.8 ± 34 [-7.61 ± 5.3] versus -65.1 ± 36 [-10.4 ± 5.6] ml/min [%], p = 0.045 [0.046]) compared to placebo group, indicating a lower basal NO activity after treatment with linagliptin. Consistently, UACR due to L-NMMA did not clearly change in linagliptin group (22.2 (11.6–40.3) versus 28.2 (16.5–50.3) mg/g, p = 0.061), but increased significantly in placebo group (13.5 (8.6–25.9) versus 20.9 (15.9–33.5) mg/g, p < 0.001), pointing to an upregulation of NO activity in the placebo group. Conclusions: Thus, our data suggest that linagliptin normalizes increased renal endothelial function, and hence NOS-dependency of vascular tone, in patients with type-2 diabetes.

AIMS:Treatment strategies for obese patients with type 2 diabetes mellitus aim to increase physical activity, reduce body weight, and improve glucose control using weight-beneficial antidiabetic drugs. The objective of this study was to determine whether these strategies are implemented, and to identify factors predictive of glucose control and body weight management in a large, real-world patient population.METHODS:The prospective DiaRegis cohort study included 3807 patients with type 2 diabetes in whom the treating physician decided to intensify and optimize treatment because of insufficient glucose control.RESULTS:Antidiabetic treatment of overweight and obese patients was compared with that of normal-weight patients over a 2-years follow-up period, and multivariate analyses were performed to identify predictors of body weight loss. Among the 3807 participants, 92.5 % were overweight or obese. Normal-weight participants were more often treated with sulfonylureas or insulin, and overweight and obese patients with metformin or glucagon-like peptide (GLP)-1 analogues. Predictors of weight loss were body mass index (BMI) ≥30 kg/m(2) and any reported physical activity.CONCLUSIONS:DiaRegis study shows that under real-world conditions, antidiabetic drug therapy is performed dependent on body weight. This strategy results in adequate glucose control and moderate weight reductions in overweight and obese patients. Weight loss is affected by treatment with weight-beneficial drugs, but also by any reported physical activity. However, only a small subgroup of patients perform physical activity. Initiation and maintenance of a physically active lifestyle remains a significant challenge for physicians, and patients with type 2 diabetes.

AIMS:There are concerns that biosimilar erythropoiesis-stimulating agents (ESAs) are less effective than the originator ESAs. The objective of our study was to investigate differences between originator and biosimilar ESA utilisation based on defined daily doses (DDD), doses upon switching, differences between short- and long-acting ESAs and prescribed daily doses (PDD) of either ESA in ambulatory patients with renal anaemia undergoing chronic maintenance haemodialysis [chronic kidney disease (CKD) stage 5].METHODS:Patients with CKD stage 5 and specific pharmacotherapy with ESAs for at least six 3-month periods (accounting quarters) were selected from a population-based database of accounting information of Bavarian physicians and pharmacy claims data (January 2008 to December 2010). The DDD was used to determine mean ESA consumption. Descriptive statistics were used to describe the results.RESULTS:In our study, 6,177 CKD stage 5 patients received ESAs for ≥6 accounting quarters, of whom 64.4 % received originator ESAs, 21.1 % received biosimilars and 14.6 % received any sequence originator and biosimilar (total of 35.7 % any biosimilar). Patients receiving either originator short-acting ESAs, long-acting darbepoetin-alfa or M-PEG epoetin-beta had a median DDD consumption of 0.77, 0.81 and 0.90, respectively. Patients receiving a biosimilar short-acting ESA had a median DDD consumption of 0.82. Doses were not increased when the therapy was switched from the originator to the biosimilar ESA. These results were confirmed in 1,886 patients receiving a continuous prescription over 12 accounting quarters, with patients receiving short-acting originator ESAs, long-acting darbepoetin-alfa and biosimilar ESAs having a median daily DDD consumption of 0.80, 0.86 and 0.81, respectively.CONCLUSIONS:We conclude that, based on a population based analysis, ESA consumption of patients on chronic haemodialysis is similar for biosimilar and originator ESAs.

The aim of this study was to compare the efficacy and tolerability of enoxaparin for preventing thromboembolism after surgery in the out-patient and in-hospital settings. A total of 2,005 out-patient and 1,360 hospitalized patients were included in the study. Prophylaxis was carried out with 20 or 40 mg enoxaparin and follow-up examination after 4-6 weeks. Out-patients were younger (mean 48.4 vs. 58.5 years, p < 0.01), had less cardiovascular comorbid diseases (7.1 vs. 20.8%, p < 0.01) and underwent less complex interventions (arthroscopy 33.6 vs. 7.5%, p < 0.01). Out-patients also received 20 instead of 40 mg enoxaparin more frequently (60.7 vs. 38.3%, p < 0.01). The mean duration of thromboprophylaxis was reduced (12.6 vs. 15.3 days). For patients treated with 20 and 40 mg minor bleeding was observed in 1.8 and 3.4%, respectively (4.7 with 20 mg and 4.5% with 40 mg in hospital), major bleeding was 0.1% for both doses in out-patients and 0.0% with 20 mg and 0.3% with 40 mg in-hospital. Deep vein thrombosis (DVT) occurred in 0.4% of out-patients receiving 20 mg enoxaparin and 0.6% with 40 mg (0.0% with 20 mg and 0.9% with 40 mg in-hospital). There were no cases of pulmonary embolism (PE) in out-patients but PE was observed in 0.2% and 0.5% with 20 mg and 40 mg in-hospital patients, respectively. Thromboprophylaxis with enoxaparin is well tolerated under clinical conditions as well as under out-patient treatment and severe bleeding complications are rare.

BACKGROUND AND PURPOSEAtrial fibrillation induces ischaemic microcirculatory flow abnormalities in the ventricle, contributing to the risk for acute coronary syndromes. We evaluated the effect of dronedarone on ventricular perfusion during rapid atrial pacing (RAP).EXPERIMENTAL APPROACHCoronary and fractional flow reserve (CFR/FFR) were measured in the left anterior descending artery in 29 pigs. Six received RAP, six received RAP with dronedarone (RAP/D), seven received dronedarone alone, four received RAP with amiodarone (RAP/A), and six received neither (sham). In ventricular tissue, oxidative stress/ischaemia‐related gene and protein expression was evaluated by RT‐PCR and Western blotting; Isoprostanes were measured by GC‐MS procedures.KEY RESULTSCFR was decreased in the RAP group, compared with other groups. FFR was not different between groups. Effective refractory period was reduced in RAP compared with RAP/D. RAP‐activated PKC phosphorylation tended to be decreased by dronedarone (P= 0.055) RAP induced NOX‐1 and NOX‐2 protein and the mRNA for hypoxia‐inducible factor‐1α (HIF‐1α). Dronedarone reduced the pacing‐dependent increase in the expression of NOX‐2 protein and of HIF‐1α mRNA. The oxidative stress marker, F2‐isoprostane, was increased by RAP and this increase was attenuated by dronedarone. Other oxidative stress/ischaemia‐related genes were induced by RAP compared with sham and were decreased by dronedarone treatment. In HL1 cells, dronedarone significantly inhibited the increased phosphorylation of PKCα after oxidative stress, with an almost significant effect (P= 0.059) on that after RAP.CONCLUSIONS AND IMPLICATIONSDronedarone abolished RAP‐induced ventricular microcirculatory abnormalities by decreasing oxidative stress/ischaemia‐related gene and protein expression in the ventricle.

Background and objective: Angioplasty in patients with renal artery stenosis aims at reducing blood pressure and at improving kidney function. Its efficacy has however been questioned by recent published data. It was the aim of this retrospective study to compare angioplasty with medical treatment in an unselected patient population.Methods: Data on 109 patients were retrospectively anlysed. This cohort included all those patients admitted to the Lippe-Detmold Hospital between 1992 and 2008 for renal artery stenosis. The data included blood pressure, creatinine-based calculated glomerular filtration rate (cGFR), any renal dialysis, cardiovascular risk factors, events and survival time after transluminal renal angioplasty or drug treatment, respectively.Results: Patients who had undergone angioplasty were younger (p = 0.04), had less cardiovascular co-morbidity (p < 0.01), but a higher degree of stenosis (p < 0.01). After a median follow-up of 32.5 (angioplasty) and 36.0 months (drug treatment), respectively, a significant decrease of cGFR was recorded in drug treated patients (- 16.2 ml/min, 95%, CI - 25.7 to - 6.7) but not in the angioplasty group (- 4.5 ml/min, 95%, CI - 13.5 to 4.5). There were no other significant differences were not observed.Conclusion: Younger patients with a high degree of renal artery stenosis but without generalized atherosclerosis more frequently underwent angioplasty in clinical practice. The smaller post-angioplasty reduction in the loss of renal function in this group needs to be validated in a prospective, randomized study.

Recently, we identified inconsistencies in the assessment of results of the CAPRIE trial by the NICE and IQWiG and asked for standards in the performance and interpretation of subgroup analyses [1A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.Lancet. 1996; 348: 1329-1339Abstract Full Text Full Text PDF PubMed Scopus (6250) Google Scholar, 2Hasford J. Lehmacher W. Benefit assessment in Germany.N Engl J Med. 2010; 362 (author reply e11): e11Crossref PubMed Google Scholar, 3Hasford J. Bramlage P. Koch G. Lehmacher W. Einhaupl K. Rothwell P.M. Inconsistent trial assessments by the National Institute for Health and Clinical Excellence and IQWiG: standards for the performance and interpretation of subgroup analyses are needed.J Clin Epidemiol. 2010; 63: 1298-1304Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. This was reflected by the conclusion of the NICE that CAPRIE demonstrated clinical benefit for the overall intention-to-treat population with sufficient robustness to possible sources of heterogeneity [[4]NICE Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events. NICE, London2005http://www.nice.org.uk/nicemedia/pdf/TA090guidance.pdfGoogle Scholar]. The IQWiG however interpreted the alleged heterogeneity as implying that the clinical benefit only applied to the subgroup of patients with a statistically significant result irrespective of the results of the intention-to-treat analysis [[5]IQWiG Final report plan for the evaluation: “clopidogrel versus acetyl salicylic acid in the secondary prevention of vascular events”. IQWiG, Cologne2006http://www.iqwig.de/download/A04-01A_Abschlussbericht_Clopidogrel_versus_ASS_in_der_Sekundaerprophylaxe.pdfGoogle Scholar]. Bender et al. disagreed with our view in their article stating in principle that different assessment goals may lead to different conclusions regarding subgroup analyses [[6]Bender R. Koch A. Skipka G. Kaiser T. Lange S. No inconsistent trial assessments by NICE and IQWiG: different assessment goals may lead to different assessment results regarding subgroup analyses.J Clin Epidemiol. 2011; 64: 451-452Abstract Full Text Full Text PDF PubMed Google Scholar]. Given that they do not address major points of our arguments, such as the explicit lack of a priori subgroup hypotheses and corresponding lack of power, we do not agree with essential parts of their statement. In addition, we note that they misinterpret aspects of our paper, for example, they wrote “Hasford et al. refer to Jackson [[7]Jackson D. The power of the standard test for the presence of heterogeneity in meta-analysis.Stat Med. 2006; 25: 2688-2699Crossref PubMed Scopus (54) Google Scholar] who proposed to use an increased significance level of alpha=0.1 for heterogeneity tests due to their low power.” suggesting that we agree with this approach. We however explicitly stated: “that the discussion (of Jackson)… has been misunderstood… Jackson wrote about the adjustments made for testing the feasibility of meta-analyses” (and not of a single randomized trial). Such misinterpretation is puzzling as the IQWiG had introduced the paper of Jackson into the discussion [[8]IQWiG Allgemeine Methoden Version 3.0 vom 27.05.2008. IQWiG, Köln2008http://www.iqwig.de/download/IQWiG_Methoden_Version_3_0.pdfGoogle Scholar]. Nevertheless, standards for the performance and interpretation of subgroup analyses are needed, and this important point is confirmed by Bender et al.: “Beyond the standards for subgroup analyses in clinical trials, new standards for the interpretation of subgroup analyses in systematic reviews are needed.” We definitely agree.

Hintergrund: Methoden: Ergebnisse: Schlussfolgerung: Background and objective: Methods: Results: Conclusion:

H ypertension affects approximately one billion adults worldwide, 1 with control rates hovering around 50% at best, 2,3 urging us to do better.On the other hand, as we strive to better manage our patients and control risk factors, emerging data highlights that our efforts are often still suboptimal.Furthermore, guidelines ask us to treat to ever-lower targets and steer us toward more stringent goals.Concerted efforts have, therefore, been initiated to reduce blood pressure levels at both the individual and the population levels. 4,5harmacotherapy for hypertension has advanced in recent years with the development of new drug classes, some of which profess to have minimal side effects, and fixed-dose combinations in a variety of cross-class combinations. 6Thus, by necessity, a great deal of focus has been cast on the intensification of therapy, which is clearly important.However, as stated by Heisler et al., 7 the decision to do so should not be based solely on blood pressure level; it must also address the ability of the patient to adhere.Compliance or adherence to antihypertensive therapy is a rich area of research, and new strategies are needed to better manage hypertensive patients by multiple approaches.These include reinforcing the patient-doctor relationship, selection of the most appropriate drug regimen, using home blood pressure monitoring as a means of patient empowerment and compliance monitoring, all of which can be implemented by a number of techniques. 8

Fragestellung: Patienten mit Typ-2-Diabetes haben ein erhöhtes Risiko für behandlungs- und krankheitsbedingte Komplikationen nach Versagen des initialen Therapieansatzes mit einer oralen antidiabetischen Mono-/Zweifachtherapie. Zur Bestimmung der Hypoglykämie Inzidenz dieser Patienten wird die deutschlandweite, prospektive Registerstudie DiaRegis durchgeführt. Bundesweit werden Patienten mit Typ 2 Diabetes in dieses Register eingeschlossen und für 2 Jahre beobachtet. Ziel der vorliegenden Analyse war die Identifizierung von Prädiktoren für die Hypoglykämie Inzidenz in den letzten 12 Monaten vor Einschluss.