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Background The optimal timing of anticoagulation following acute ischaemic stroke or TIA in patients with atrial fibrillation (AF) is a frequent challenge. Early initiation of anticoagulation can reduce the risk for recurrent ischaemic events, but may lead to an increased risk for intracerebral haemorrhage. Aim The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study was initiated to investigate outcome events under antithrombotic therapy after ischaemic stroke or TIA in patients with AF. The main objective is to compare the three-month rates of major haemorrhagic events between early (≤ 7 days) versus late (> 7 days) administration of dabigatran or treatment with vitamin-K antagonists started at any time. Occurrences of ischaemic and major haemorrhagic events will be evaluated to determine the optimal time point for initiation or resumption of anticoagulation. Design and Methods PRODAST is a prospective, multicenter, observational, non-interventional post-authorization safety study. 10,000 patients with recent (≤ 1 week from index event) ischaemic stroke or TIA and non-valvular AF were recruited at 86 German sites starting in July 2015. The observational plan includes a baseline visit, documentation of data during hospitalization and a telephone-based, central follow-up at three months after the index event. The primary endpoint is the major bleeding rate within three months. Secondary endpoints include rates of recurrent ischaemic or haemorrhagic stroke, TIA, systemic embolism, myocardial infarction and death. Summary PRODAST will provide important real-world data on safety and efficacy of antithrombotic therapy after acute stroke and TIA in patients with AF.

Cold agglutinin disease (CAD) is a complement-dependent disorder, with extravascular and intravascular hemolysis resulting from initial or terminal complement activation, respectively. We tested the efficacy and safety of eculizumab, an inhibitor of the terminal complement pathway. Treatment-requiring patients received 600 mg eculizumab weekly for 4 weeks, followed 1 week later by 900 mg every other week through week 26. The primary end point was the difference in the lactate dehydrogenase level between the first and the last day of therapy. Twelve patients with chronic CAD and 1 patient with an acute cold agglutinin syndrome were included. The median lactate dehydrogenase level decreased from 572 U/L (interquartile range [IQR], 534-685) to 334 U/L (IQR, 243-567; P = .0215), paralleled by an increase in hemoglobin from 9.35 g/dL (IQR, 8.80-10.80) to 10.15 g/dL (IQR, 9.00-11.35; P = .0391; Wilcoxon signed-rank test). Three patients maintained and 8 patients acquired transfusion independence, and 1 patient each showed a reduced or increased transfusion requirement, respectively (P = .0215; exact McNemar’s test). Patients with cold agglutinins with a thermal amplitude of 37°C tended to have less pronounced lactate dehydrogenase responses than patients with cold agglutinins with narrower thermal amplitudes. In the latter, responses were observed at lower serum levels of eculizumab than they were in the former. In contrast to hemolysis, cold-induced circulatory symptoms remained unaffected. In conclusion, eculizumab significantly reduced hemolysis and transfusion requirement in patients with CAD. Suppression of hemolysis caused by cold agglutinins with a wide thermal amplitude may require higher eculizumab doses than used here. The trial is registered with EudraCT (#2009-016966-97) and www.clinicaltrials.gov (#NCT01303952).

Several dimensions of data quality are described in the literature. One overriding aspect is considered to be the extent to which data represent the truth which is captured by data validity. Unfortunately, a common terminology, well defined concepts, and approved measures are missing in regard to data validity. In particular, there is a need to discuss the gold standard as reference for the data at hand and respective measures. Ultimate gold standard would be the state of the patient which itself is subjected to human and personal interpretations. Usually, an often diverse form of source data is used as gold standard. Based on the concept of the measure, it might be inappropriate differentiating between present and absent while calculating precision and recall. Due to the complexity and uncertainty of many health care related issues, a more sophisticated comparison might be necessary in order to establish relevant and general figures of data quality. Unfortunately, a harmonization in this field is not visible. Further research is needed to establish validated standards to measure data quality.

Objective: Adverse drug events (ADEs) during hospital stays are a significant problem of healthcare systems. Established monitoring systems lack completeness or are cost intensive. Routinely assigned International Statistical Classification of Diseases and Related Health Problems (ICD) codes could complement existing systems for ADE identification. To analyze the potential of using routine data for ADE detection, the validity of a set of ICD codes was determined focusing on hospital-acquired events. Material and methods: The study utilized routine data from four German hospitals covering the years 2014 and 2015. A set of ICD, 10th Revision, German Modification (ICD-10-GM) diagnoses coded most frequently in the routine data and identified as codes indicating ADEs was analyzed. Data from psychiatric and psychotherapeutic departments were excluded. Retrospective chart review was performed to calculate positive predictive values (PPV) and sensitivity. Results: Of 807 reviewed ADE codes, 91.2% (95%-confidence interval: 89.0, 93.1) were identified as disease in the medical records and 65.1% (61.7, 68.3) were confirmed as ADE. For code groups being predominantly hospital-acquired, 78.5% (73.7, 82.9) were confirmed as ADE, ranging from 68.5% to 94.4% dependent on the ICD code. However, sensitivity of inpatient ADEs was relatively low. 49.7% (45.2, 54.2) of 495 identified hospital-acquired ADEs were coded as disease in the routine data, from which a subgroup of 12.1% (9.4, 15.3) was coded as drug-associated disease. Conclusions: ICD codes from routine data can provide an important contribution to the development and improvement of ADE monitoring systems. Documentation quality is crucial to further increase the PPV, and actions against under-reporting of ADEs in routine data need to be taken. © 2017 Kuklik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. OA gold

BACKGROUND: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia characterized by hemagglutination and complement-mediated extra- and intravascular hemolysis. Conventional therapeutic approaches, such as corticosteroids, intravenous immunoglobulin G, alkylating agents or other immunosuppressive drugs, are largely ineffective, and the therapeutic efficacy of rituximab is limited. Successful treatment of a patient with CAD with the terminal complement inhibitor eculizumab reported by us previously (Röth et al., Blood 2009) prompted us to test this novel approach in a larger number of patients. PATIENTS and METHODS: We conducted a prospective, controlled, non-randomized, multicenter phase II trial with pre- and post-treatment comparison. Inclusion criteria were symptomatic cold agglutinin-mediated hemolysis with a serum lactate dehydrogenase (LDH) level ≥ 2 x upper limit of normal and a cold agglutinin titer > 64 at 4°C. Eculizumab was given by intravenous infusion at 600 mg weekly for 4 weeks, followed 1 week later by a 900 mg dose and then 900 mg every other week through week 26. Two weeks before the first dose patients received vaccination against N. meningitidis. The primary endpoint was LDH level, secondary endpoints included transfusion requirements, parameters of intravascular hemolysis, quality of life, 6-minute walk test (6MWT), circulatory symptoms and thrombosis. The analysis was performed in the intent-to-treat population. Missing data were replaced by carrying the last observation forward. The trial was registered at http://clinicaltrials.gov as NCT01303952. RESULTS: Between 2011 and 2014 13 treatment-naïve or pretreated patients with CAD were enrolled. The median age was 74 years (range: 64 - 80), with a male-to-female ratio of 3 to 10. After treatment with eculizumab the LDH decreased from a median pre-treatment level of 572 U/L (mean ± standard deviation: 670 ± 300 U/L) by an average of 56% to a median end-of-treatment level of 327 U/L (400 ± 279 U/L; p = 0.0215, Wilcoxon signed-rank test). This was accompanied by a reduction in transfusion requirement from a median of 4.0 red blood cell units per patient in the 12-month period preceding participation in the study to 0.0 units during treatment with eculizumab. In 9 patients, transfusion requirements decreased during eculizumab therapy, in 3 patients, transfusions were required neither before nor during the study, and in one patient, transfusion requirement deteriorated (p = 0.0215, Exact McNemar's test). The result of the 6MWT improved from a median of 358 m at baseline to a median of 420 m at the end of treatment (p = 0.078). Questionnaires for quality of life showed no significant changes. During the enrollment phase, 7 thromboembolic events including 1 pulmonary embolism were recorded in a total of 4 patients; by contrast, no thromboembolic events were observed during treatment with eculizumab. A total of 37 adverse events were reported of which one was considered as probably related to eculizumab (pneumonia, patient recovered). All in all, 57% of adverse events were classified as unrelated, 5% as unlikely to be related, 32% as possibly related, and 3% as probably related to treatment. There were 4 serious adverse events. CONCLUSIONS: Treatment with eculizumab was safe and well tolerated in patients with CAD. It resulted in a statistically significant reduction in hemolysis and transfusion requirements and appeared to have a favorable impact on thromboembolic complications. The results of this trial support the notion that terminal complement activation is a relevant mediator of erythrocyte destruction in CAD. Disclosures Röth: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding. Off Label Use: Use of eculizumab in CAD. Bommer:Alexion Pharmaceuticals: Honoraria. Hüttmann:Celgene: Other: Travel support, Speakers Bureau; Takeda: Consultancy, Other: Travel support; Gilead: Consultancy; Amgen: Consultancy, Research Funding; Roche: Research Funding. Schrezenmeier:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dührsen:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding.