Conditional survival to assess prognosis in patients with chronic lymphocytic leukemia.

Biomarkers in chronic lymphocytic leukemia (CLL) allow assessment of prognosis. However, the validity of current prognostic biomarkers based on a single assessment point remains unclear for patients who have survived one or more years. Conditional survival (CS) studies that address how prognosis may change over time, especially in prognostic subgroups, are still rare. We performed CS analyses to estimate 5-year survival in 1-year increments, stratified by baseline disease characteristics and known risk factors in two community-based cohorts of CLL patients (Freiburg University Hospital (n = 316) and Augsburg University Hospital (n = 564)) diagnosed between 1984 and 2021. We demonstrate that 5-year CS probability is stable (app. 75%) for the entire CLL patient cohort over 10 years. While age, sex, and stage have no significant impact on CS, patients with high-risk disease features such as non-mutated IGHV, deletion 17p, and high-risk CLL-IPI have a significantly worse prognosis at diagnosis, and 5-year CS steadily decreases with each additional year survived. Our results confirm that CLL patients have a stable survival probability with excess mortality and that the prognosis of high-risk CLL patients declines over time. We infer that CS-based prognostic information is relevant for disease management and counseling of CLL patients.

[Quality Indicators Show Higher Fulfilment in Centers Certified by the German Cancer Society]. / Qualitätsindikatoren zeigen bessere Erfüllungsquoten in DKG-zertifizierten Zentren.

AIM: In 2003, a certification program was introduced by the German Cancer Society in Germany to ensure high standards of oncological care. The present study investigated whether there were differences in the concordance to guideline-based recommendations between centers certified by the German Cancer Society and medical facilities without such certification. In this context, quality indicators derived from clinical guidelines were evaluated. METHODS: The database of the cancer registry of Rhineland-Palatinate, Germany was used to calculate fulfilment of target values for 14 quality indicators. Analysis of quality indicators followed specifications given in treatment S3-guidelines for breast, colorectal and lung cancer. Analyses were done by R and SAS. RESULTS: All 14 quality indicators showed that concordance with guideline-based recommendations was higher in certified centers compared to uncertified medical facilities; 13 of these differences were statistically significant. CONCLUSION: Higher quality of oncological treatment in certified centers has widely been discussed in the WiZen study. The results of our study support this assumption with respect to concordance with quality indicators.

Simplification of soil biota communities impairs nutrient recycling and enhances above- and belowground nitrogen losses.

Agriculture is a major source of nutrient pollution, posing a threat to the earth system functioning. Factors determining the nutrient use efficiency of plant-soil systems need to be identified to develop strategies to reduce nutrient losses while ensuring crop productivity. The potential of soil biota to tighten nutrient cycles by improving plant nutrition and reducing soil nutrient losses is still poorly understood. We manipulated soil biota communities in outdoor lysimeters, planted maize, continuously collected leachates, and measured N2 O- and N2 -gas emissions after a fertilization pulse to test whether differences in soil biota communities affected nutrient recycling and N losses. Lysimeters with strongly simplified soil biota communities showed reduced crop N (-20%) and P (-58%) uptake, strongly increased N leaching losses (+65%), and gaseous emissions (+97%) of N2 O and N2 . Soil metagenomic analyses revealed differences in the abundance of genes responsible for nutrient uptake, nitrate reduction, and denitrification that helped explain the observed nutrient losses. Soil biota are major drivers of nutrient cycling and reductions in the diversity or abundance of certain groups (e.g. through land-use intensification) can disrupt nutrient cycling, reduce agricultural productivity and nutrient use efficiency, and exacerbate environmental pollution and global warming.

Deterministic Development of Soil Microbial Communities in Disturbed Soils Depends on Microbial Biomass of the Bioinoculum.

Despite its enormous importance for ecosystem services, factors driving microbial recolonization of soils after disturbance are still poorly understood. Here, we compared the microbial recolonization patterns of a disturbed, autoclaved soil using different amounts of the original non-disturbed soil as inoculum. By using this approach, we manipulated microbial biomass, but did not change microbial diversity of the inoculum. We followed the development of a new soil microbiome after reinoculation over a period of 4 weeks using a molecular barcoding approach as well as qPCR. Focus was given on the assessment of bacteria and archaea. We could show that 1 week after inoculation in all inoculated treatments bacterial biomass exceeded the values from the original soil as a consequence of high dissolved organic carbon (DOC) concentrations in the disturbed soil resulting from the disturbance. This high biomass was persistent over the complete experimental period. In line with the high DOC concentrations, in the first 2 weeks of incubation, copiotrophic bacteria dominated the community, which derived from the inoculum used. Only in the disturbed control soils which did not receive a microbial inoculum, recolonization pattern differed. In contrast, archaeal biomass did not recover over the experimental period and recolonization was strongly triggered by amount of inoculated original soil added. Interestingly, the variability between replicates of the same inoculation density decreased with increasing biomass in the inoculum, indicating a deterministic development of soil microbiomes if higher numbers of cells are used for reinoculation.

Genotypic and phenotypic characterization of hydrogenotrophic denitrifiers.

Stimulating litho-autotrophic denitrification in aquifers with hydrogen is a promising strategy to remove excess NO3 - , but it often entails accumulation of the cytotoxic intermediate NO2 - and the greenhouse gas N2 O. To explore if these high NO2 - and N2 O concentrations are caused by differences in the genomic composition, the regulation of gene transcription or the kinetics of the reductases involved, we isolated hydrogenotrophic denitrifiers from a polluted aquifer, performed whole-genome sequencing and investigated their phenotypes. We therefore assessed the kinetics of NO2 - , NO, N2 O, N2 and O2 as they depleted O2 and transitioned to denitrification with NO3 - as the only electron acceptor and hydrogen as the electron donor. Isolates with a complete denitrification pathway, although differing intermediate accumulation, were closely related to Dechloromonas denitrificans, Ferribacterium limneticum or Hydrogenophaga taeniospiralis. High NO2 - accumulation was associated with the reductases' kinetics. While available, electrons only flowed towards NO3 - in the narG-containing H. taeniospiralis but flowed concurrently to all denitrification intermediates in the napA-containing D. denitrificans and F. limneticum. The denitrification regulator RegAB, present in the napA strains, may further secure low intermediate accumulation. High N2 O accumulation only occurred during the transition to denitrification and is thus likely caused by delayed N2 O reductase expression.

Carbohydrate depletion in roots impedes phosphorus nutrition in young forest trees.

Nutrient imbalances cause the deterioration of tree health in European forests, but the underlying physiological mechanisms are unknown. Here, we investigated the consequences of decreasing root carbohydrate reserves for phosphorus (P) mobilisation and uptake by forest trees. In P-rich and P-poor beech (Fagus sylvatica) forests, naturally grown, young trees were girdled and used to determine root, ectomycorrhizal and microbial activities related to P mobilisation in the organic layer and mineral topsoil in comparison with those in nongirdled trees. After girdling, root carbohydrate reserves decreased. Root phosphoenolpyruvate carboxylase activities linking carbon and P metabolism increased. Root and ectomycorrhizal phosphatase activities and the abundances of bacterial genes catalysing major steps in P turnover increased, but soil enzymes involved in P mobilisation were unaffected. The physiological responses to girdling were stronger in P-poor than in P-rich forests. P uptake was decreased after girdling. The soluble and total P concentrations in roots were stable, but fine root biomass declined after girdling. Our results support that carbohydrate depletion results in reduced P uptake, enhanced internal P remobilisation and root biomass trade-off to compensate for the P shortage. As reductions in root biomass render trees more susceptible to drought, our results link tree deterioration with disturbances in the P supply as a consequence of decreased belowground carbohydrate allocation.

A multicentre analytical comparison study of inter-reader and inter-assay agreement of four programmed death-ligand 1 immunohistochemistry assays for scoring in triple-negative breast cancer.

AIMS: Studies in various cancer types have demonstrated discordance between results from different programmed death-ligand 1 (PD-L1) assays. Here, we compare the reproducibility and analytical concordance of four clinically developed assays for assessing PD-L1-positivity in tumour-infiltrating immune cells in the tumour area (PD-L1-IC-positivity) in triple-negative breast cancer (TNBC). METHODS AND RESULTS: Primary TNBC resection specimens (n = 30) were selected based on their PD-L1-IC-positivity per VENTANA SP142 (<1%: 15 cases; 1-5%: seven cases; >5%: eight cases). Serial histological sections were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3 and DAKO 28-8. PD-L1-IC-positivity and tumour cell expression (≥1 versus <1%) were scored by trained readers from seven sites using online virtual microscopy. The adjusted mean of PD-L1-IC-positivity for SP263 (7.8%) was significantly higher than those for the other three assays (3.7-4.9%). Differences in adjusted means were statistically significant between SP263 and the other three assays (P < 0.0001) but not between the three remaining assays when excluding SP263 (P = 0.0961-0.6522). Intra-class correlation coefficients revealed moderate-to-strong inter-reader agreement for each assay (0.460-0.805) and poor-to-strong inter-assay agreement for each reader (0.298-0.678) on PD-L1-IC-positivity. CONCLUSIONS: In this first multicentre study of different PD-L1 assays in TNBC, we show that PD-L1-IC-positivity for SP142, 22C3 and 28-8 was reproducible and analytically concordant, indicating that these three assays may be analytically interchangeable. The relevance of the higher PD-L1-IC-positivity for SP263 should be further investigated.

Microbial Key Players Involved in P Turnover Differ in Artificial Soil Mixtures Depending on Clay Mineral Composition.

Nutrient turnover in soils is strongly driven by soil properties, including clay mineral composition. One main nutrient is phosphorus (P), which is known to be easily immobilized in soil. Therefore, the specific surface characteristics of clay minerals might substantially influence P availability in soil and thus the microbial strategies for accessing P pools. We used a metagenomic approach to analyze the microbial potential to access P after 842 days of incubation in artificial soils with a clay mineral composition of either non-expandable illite (IL) or expandable montmorillonite (MT), which differ in their surface characteristics like soil surface area and surface charge. Our data indicate that microorganisms of the two soils developed different strategies to overcome P depletion, resulting in similar total P concentrations. Genes predicted to encode inorganic pyrophosphatase (ppa), exopolyphosphatase (ppx), and the pstSCAB transport system were higher in MT, suggesting effective P uptake and the use of internal poly-P stores. Genes predicted to encode enzymes involved in organic P turnover like alkaline phosphatases (phoA, phoD) and glycerophosphoryl diester phosphodiesterase were detected in both soils in comparable numbers. In addition, Po concentrations did not differ significantly. Most identified genes were assigned to microbial lineages generally abundant in agricultural fields, but some were assigned to lineages known to include oligotrophic specialists, such as Bacillaceae and Microchaetaceae.

Biological Soil Crusts from Different Soil Substrates Harbor Distinct Bacterial Groups with the Potential to Produce Exopolysaccharides and Lipopolysaccharides.

Biological soil crusts (biocrusts) play an important role in improving soil stability and resistance to erosion by promoting aggregation of soil particles. During initial development, biocrusts are dominated by bacteria. Some bacterial members of the biocrusts can contribute to the formation of soil aggregates by producing exopolysaccharides and lipopolysaccharides that act as "glue" for soil particles. However, little is known about the dynamics of "soil glue" producers during the initial development of biocrusts. We hypothesized that different types of initial biocrusts harbor distinct producers of adhesive polysaccharides. To investigate this, we performed a microcosm experiment, cultivating biocrusts on two soil substrates. High-throughput shotgun sequencing was used to obtain metagenomic information on microbiomes of bulk soils from the beginning of the experiment, and biocrusts sampled after 4 and 10 months of incubation. We discovered that the relative abundance of genes involved in the biosynthesis of exopolysaccharides and lipopolysaccharides increased in biocrusts compared with bulk soils. At the same time, communities of potential "soil glue" producers that were highly similar in bulk soils underwent differentiation once biocrusts started to develop. In the bulk soils, the investigated genes were harbored mainly by Betaproteobacteria, whereas in the biocrusts, the major potential producers of adhesive polysaccharides were, aside from Alphaproteobacteria, either Cyanobacteria or Chloroflexi and Acidobacteria. Overall, our results indicate that the potential to form exopolysaccharides and lipopolysaccharides is an important bacterial trait for initial biocrusts and is maintained despite the shifts in bacterial community composition during biocrust development.

Design of a non-interventional post-marketing study to assess the long-term safety and effectiveness of ocrelizumab in German real world multiple sclerosis cohorts - the CONFIDENCE study protocol.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease that requires lifelong treatment. A highly effective drug not only for relapsing but also for progressive forms of MS with a favorable safety profile is needed to further improve overall patient outcomes. Ocrelizumab, a recombinant humanized monoclonal antibody that selectively targets CD20-expressing B-cells, is the first drug indicated for the treatment of adult patients with relapsing forms of MS (RMS) and primary progressive MS (PPMS). Its safety and effectiveness profile has yet to be studied in a large, real-world setting. CONFIDENCE aims to further characterize the safety profile of ocrelizumab in routine clinical practice. In addition, real-world effectiveness data will be collected to complement the efficacy data documented in the pivotal clinical trials. METHODS: CONFIDENCE is a non-interventional, prospective, multicenter, long-term study collecting primary data from 3000 RMS and PPMS patients newly treated with ocrelizumab and 1500 patients newly treated with other selected MS disease-modifying therapies (DMTs). Treatment must be in accordance with the local label and follow routine practice. Data will be collected at approximately 250 neurological centers and practices across Germany. The recruitment period of 30 months started in April 2018. The observation period per patient is planned 7.5 to 10 years, depending on the date of inclusion, regardless of whether patients discontinue treatment. Visits follow routine practice and will be documented approximately every 6 months. The primary endpoint is the incidence and type of uncommon adverse events and death. Statistical analyses will be mainly descriptive and exploratory. DISCUSSION: CONFIDENCE is a large, non-interventional, post-authorization safety study that assesses long-term safety and effectiveness of ocrelizumab and other DMTs in a real-world setting. Data collected in CONFIDENCE will also be integrated into studies that have been developed to fulfil international regulatory requirements.

Long-term effects of environmentally relevant concentrations of silver nanoparticles on microbial biomass, enzyme activity, and functional genes involved in the nitrogen cycle of loamy soil.

The increasing production and use of engineered silver nanoparticles (AgNP) in industry and private households are leading to increased concentrations of AgNP in the environment. An ecological risk assessment of AgNP is needed, but it requires understanding the long term effects of environmentally relevant concentrations of AgNP on the soil microbiome. Hence, the aim of this study was to reveal the long-term effects of AgNP on soil microorganisms. The study was conducted as a laboratory incubation experiment over a period of one year using a loamy soil and AgNP concentrations ranging from 0.01 to 1 mg AgNP/kg soil. The short term effects of AgNP were, in general, limited. However, after one year of exposure to 0.01 mg AgNP/kg, there were significant negative effects on soil microbial biomass (quantified by extractable DNA; p = 0.000) and bacterial ammonia oxidizers (quantified by amoA gene copy numbers; p = 0.009). Furthermore, the tested AgNP concentrations significantly decreased the soil microbial biomass, the leucine aminopeptidase activity (quantified by substrate turnover; p = 0.014), and the abundance of nitrogen fixing microorganisms (quantified by nifH gene copy numbers; p = 0.001). The results of the positive control with AgNO3 revealed predominantly stronger effects due to Ag+ ion release. Thus, the increasing toxicity of AgNP during the test period may reflect the long-term release of Ag+ ions. Nevertheless, even very low concentrations of AgNP caused disadvantages for the microbial soil community, especially for nitrogen cycling, and our results confirmed the risks of releasing AgNP into the environment.

Field-Scale Pattern of Denitrifying Microorganisms and N2O Emission Rates Indicate a High Potential for Complete Denitrification in an Agriculturally Used Organic Soil.

More than 50% of all anthropogenic N2O emissions come from the soil. Drained Histosols that are used for agricultural purposes are particularly potent sources of denitrification due to higher stocks of organic matter and fertiliser application. However, conditions that favour denitrification can vary considerably across a field and change significantly throughout the year. Spatial and temporal denitrifier dynamics were assessed in a drained, intensely managed Histosol by focusing on the genetic nitrite and N2O reduction potential derived from the abundance of nirK, nirS and nosZ genes. These data were correlated with soil properties at two different points in time in 2013. N2O emissions were measured every 2 weeks over three vegetation periods (2012-2014). Very low N2O emission rates were measured throughout the entire period of investigation in accordance with the geostatistical data that revealed an abundance of microbes carrying the N2O reductase gene nosZ. This, along with neutral soil pH values, is indicative of high microbial denitrification potential. While the distribution of the microbial communities was strongly influenced by total organic carbon and nitrogen pools in March, the spatial distribution pattern was not related to the distribution of soil properties in October, when higher nutrient availability was observed. Different nitrite reducer groups prevailed in spring and autumn. While nirS, followed by nosZ and nirK, was most abundant in March, the latter was the dominant nitrite reductase in October.

Phosphorus depletion in forest soils shapes bacterial communities towards phosphorus recycling systems.

Phosphorus (P) is an important macronutrient for all biota on earth but similarly a finite resource. Microorganisms play on both sides of the fence as they effectively mineralize organic and solubilize precipitated forms of soil phosphorus but conversely also take up and immobilize P. Therefore, we analysed the role of microbes in two beech forest soils with high and low P content by direct sequencing of metagenomic deoxyribonucleic acid. For inorganic P solubilization, a significantly higher microbial potential was detected in the P-rich soil. This trait especially referred to Candidatus Solibacter usiatus, likewise one of the dominating species in the data sets. A higher microbial potential for efficient phosphate uptake systems (pstSCAB) was detected in the P-depleted soil. Genes involved in P starvation response regulation (phoB, phoR) were prevalent in both soils. This underlines the importance of effective phosphate (Pho) regulon control for microorganisms to use alternative P sources during phosphate limitation. Predicted genes were primarily harboured by Rhizobiales, Actinomycetales and Acidobacteriales.

Weight of the bleeding impact on early and late mortality after percutaneous coronary intervention.

The association between bleeding and timing of mortality after percutaneous coronary intervention (PCI) remains poorly investigated. We aimed to investigate the impact of bleeding on early (30-day) and late (30-day to 1 year) mortality after PCI. The study includes 14,180 patients. Bleeding within 30 days after PCI was defined using the Bleeding Academic Research Consortium criteria. Landmark analysis pre-specified at 1 month was performed to assess early and late mortality associated with bleeding. The main outcome was all-cause early and late mortality after PCI. Overall, 414 patients (2.9 %) died within the first year after PCI. Within 30 days after PCI there were 36 deaths among patients with bleeding (n = 1,510) and 44 deaths among patients without bleeding (n = 12,670; Kaplan-Meier [KM] estimates of mortality, 2.4 and 0.3 %; adjusted hazard ratio [HR] = 5.00, 95 % confidence interval 3.16-7.88, P < 0.001). In the 30-day to 1-year period there were 68 deaths among patients with bleeding and 266 deaths among patients without bleeding (KM estimates, 4.7 and 2.1 %; adjusted HR = 1.65 [1.25-2.17], P < 0.001. Bleeding was the strongest correlate of 30-day mortality. The association of bleeding with late mortality was significant but was weaker than that of age, diabetes, C-reactive protein, serum creatinine and platelet count. In conclusion, patients with bleeding after PCI continue to be at higher risk of early and late mortality compared to patients without bleeding. Bleeding was the strongest associate of early mortality whereas the increased risk for late mortality was mostly mediated by cardiovascular risk factors clustered in patients with bleeding.

Predictors of antiplatelet response to prasugrel during maintenance treatment.

Insufficient P2Y12 receptor inhibition is associated with a higher risk of thrombotic events after percutaneous coronary intervention (PCI). The third generation thienopyridine prasugrel achieves stronger platelet inhibition as compared to its predecessor clopidogrel. Little is known about predictors of prasugrel drug responsiveness. The aim of this study was to explore predictors of prasugrel responsiveness in patients with a recent PCI on prasugrel maintenance dose (MD) treatment. In a registry of PCI-treated patients (n = 163, recruited between August 2009 and March 2012) on prasugrel MD treatment, the ADP-induced platelet aggregation (PA) was assessed on a Multiplate analyzer. The mean (interquartile range (IQR)) ADP-induced PA on prasugrel MD treatment was 206 (138-331) AU × min. Obese (defined by a body mass index (BMI) ≥ 30) patients (n = 42) (303 [192-467] vs. 187 [117-305] AU × min, p = 0.0001), patients (n = 70) with a history of clopidogrel low responsiveness (278 [161-409] vs. 192 [126-282] AU × min, p = 0.002) and patients (n = 18) on a low (5 mg) prasugrel MD (483 [252-798] vs. 198 [133-313] AU × min; p = 0.0001) showed higher PA values on prasugrel MD as compared to the remaining patients. In a multivariable linear regression model, the latter three variables were independently associated with higher PA values on prasugrel MD treatment. In summary response variability is observed in patients on prasugrel MD treatment. Obesity, a history of clopidogrel low responsiveness and a reduced prasugrel MD of 5 mg are independent predictors of an attenuated response to prasugrel treatment. Further studies are needed to explore clinical implications of this observation.

Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction.

AIMS: Whether prasugrel plus bivalirudin is a superior strategy to unfractionated heparin plus clopidogrel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) has never been assessed in specifically designed randomized trials. METHODS AND RESULTS: The Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 study is an investigator-initiated, randomized, open-label, multicentre trial, designed to test the hypothesis that in STEMI patients with planned primary PCI a strategy based on prasugrel plus bivalirudin is superior to a strategy based on clopidogrel plus heparin in terms of net clinical outcome. Owing to slow recruitment, the trial was stopped prematurely after enrolment of 548 of 1240 planned patients. At 30 days, the primary composite endpoint of death, myocardial infarction, unplanned revascularization of the infarct related artery, stent thrombosis, stroke, or bleeding was observed in 42 patients (15.6%) randomized to prasugrel plus bivalirudin and 40 patients (14.5%) randomized to clopidogrel plus heparin [relative risk, 1.09; one-sided 97.5% confidence interval (CI) 0-1.79, P = 0.680]. The composite ischaemic endpoint of death, myocardial infarction, unplanned revascularization of the infarct-related artery, stent thrombosis, or stroke occurred in 13 patients (4.8%) in the prasugrel plus bivalirudin group and 15 patients (5.5%) in the clopidogrel plus heparin group (relative risk, 0.89; 95% CI 0.40-1.96, P = 0.894). Bleeding according to the HORIZONS-AMI definition was observed in 38 patients (14.1%) in the prasugrel plus bivalirudin group and 33 patients (12.0%) in the clopidogrel plus heparin group (relative risk, 1.18; 95% CI 0.74-1.88, P = 0.543). Results were consistent across various subgroups of patients. CONCLUSION: In this randomized trial of STEMI patients, we were unable to demonstrate significant differences in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus heparin. Neither the composite of ischaemic complications nor bleeding were favourably affected by prasugrel plus bivalirudin compared with a regimen of clopidogrel plus unfractionated heparin. However, the results must be interpreted in view of the premature termination of the trial. CLINICAL TRIAL REGISTRATION INFORMATION: Unique identifier NCT00976092 (www.clinicaltrials.gov).

Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial.

BACKGROUND: The best way to manage restenosis in patients who have previously received a drug-eluting stent is unknown. We investigated the efficacy of paclitaxel-eluting balloons (PEB), paclitaxel-eluting stents (PES), and balloon angioplasty in these patients. METHODS: In this randomised, open-label trial, we enrolled patients older than 18 years with restenosis of at least 50% after implantation of any limus-eluting stent at three centres in Germany between Aug 3, 2009, and Oct 27, 2011. Patients were randomly assigned (1:1:1; stratified according to centre) to receive PEB, PES, or balloon angioplasty alone by means of sealed, opaque envelopes containing a computer-generated sequence. Patients and investigators were not masked to treatment allocation, but events and angiograms were assessed by individuals who were masked. The primary endpoint was diameter stenosis at follow-up angiography at 6-8 months. Primary analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00987324. FINDINGS: We enrolled 402 patients, of whom 137 (34%) were assigned to PEB, 131 (33%) to PES, and 134 (33%) to balloon angioplasty. Follow-up angiography at 6-8 months was available for 338 (84%) patients. PEB was non-inferior to PES in terms of diameter stenosis (38·0% [SD 21·5] vs 37·4% [21·8]; difference 0·6%, one-sided 95% CI 4·9%; p(non-inferiority)=0·007; non-inferiority margin of 7%). Findings were consistent in per-protocol analysis (p(non-inferiority)=0·011). PEB and PES were superior to balloon angioplasty alone (54·1% [25·0]; p(superiority)<0·0001 for both comparisons). Frequency of death, myocardial infarction, or target lesion thrombosis did not differ between groups. INTERPRETATION: By obviating the need for additional stent implantation, PEB could be a useful treatment for patients with restenosis after implantation of a drug-eluting stent. FUNDING: Deutsches Herzzentrum.

Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction.

BACKGROUND: The combination of glycoprotein IIb/IIIa inhibitors and heparin has not been compared with bivalirudin in studies specifically involving patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). We compared the two treatments in this patient population. METHODS: Immediately before PCI, we randomly assigned, in a double-blind manner, 1721 patients with acute non-ST-segment elevation myocardial infarction to receive abciximab plus unfractionated heparin (861 patients) or bivalirudin (860 patients). The study tested the hypothesis that abciximab and heparin would be superior to bivalirudin with respect to the primary composite end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days. Secondary end points included the composite of death, any recurrent myocardial infarction, or urgent target-vessel revascularization (efficacy end point) and major bleeding (safety end point) within 30 days. RESULTS: The primary end point occurred in 10.9% of the patients in the abciximab group (94 patients) and in 11.0% in the bivalirudin group (95 patients) (relative risk with abciximab, 0.99; 95% confidence interval [CI], 0.74 to 1.32; P=0.94). Death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the patients in the abciximab group (110 patients) and in 13.4% in the bivalirudin group (115 patients) (relative risk, 0.96; 95% CI, 0.74 to 1.25; P=0.76). Major bleeding occurred in 4.6% of the patients in the abciximab group (40 patients) as compared with 2.6% in the bivalirudin group (22 patients) (relative risk, 1.84; 95% CI, 1.10 to 3.07; P=0.02). CONCLUSIONS: Abciximab and unfractionated heparin, as compared with bivalirudin, failed to reduce the rate of the primary end point and increased the risk of bleeding among patients with non-ST-segment elevation myocardial infarction who were undergoing PCI. (Funded by Nycomed Pharma and others; ISAR-REACT 4 ClinicalTrials.gov number, NCT00373451.).

Rationale and design of The Intracoronary Stenting and Antithrombotic Regimen-Testing of a six-week versus a six-month clopidogrel treatment Regimen In Patients with concomitant aspirin and oraL anticoagulant therapy following drug-Eluting stenting (ISAR-TRIPLE) study.

BACKGROUND: An increasing number of patients undergoing coronary stenting need lifelong anticoagulation and therefore require a triple therapy typically consisting of aspirin, clopidogrel, and a vitamin K antagonist. Triple therapy confers an elevated bleeding risk as compared with dual therapy; however, omission of either antiplatelet or anticoagulation therapy might increase the risk of stent thrombosis or thrombembolic events. Although guidelines recommend a duration of dual antiplatelet therapy of 6 to 12months after drug-eluting stent (DES) implantation, the optimal duration of dual antiplatelet therapy in patients receiving oral anticoagulation is not known. HYPOTHESIS: We postulate that 6-week clopidogrel therapy after DES implantation as compared with 6-month therapy is associated with improved clinical outcomes in patients undergoing DES implantation receiving concomitant aspirin and vitamin K antagonists. STUDY DESIGN: The ISAR-TRIPLE is a randomized, open-label trial that examines the restriction of clopidogrel therapy from 6 months to 6 weeks after DES implantation in the setting of concomitant aspirin and oral anticoagulant. Patients are randomized in a 1:1 fashion to either 6-week or 6-month clopidogrel therapy. The primary end point is a composite of death, myocardial infarction, definite stent thrombosis, stroke, or major bleeding. The secondary end point comprises ischemic and bleeding complications. According to sample size calculations, a total of 600 patients are required to be enrolled. Clinical follow-up is scheduled at 6 weeks and at 6 and 9 months after randomization. SUMMARY: There is clinical equipoise regarding the optimal duration of triple therapy after DES implantation in patients who need vitamin K antagonist therapy. The ISAR-TRIPLE trial aims to test the hypothesis that a 6-week triple therapy compared with a 6-month triple therapy improves net clinical outcomes.