In vitro fertilization exacerbates stroke size and neurological disability in wildtype mice.

BACKGROUND AND PURPOSE: Assisted reproductive technologies (ART) induce premature vascular aging in human offspring. The related alterations are well-established risk factors for stroke and predictors of adverse stroke outcome. However, given the young age of the human ART population there is no information on the incidence and outcome of cerebrovascular complications in humans. In mice, ART alters the cardiovascular phenotype similarly to humans, thereby offering the possibility to study this problem. METHODS: We investigated the morphological and clinical outcome after ischemia/reperfusion brain injury induced by transient (45 min) middle cerebral artery occlusion in ART and control mice. RESULTS: We found that stroke volumes were almost 3-fold larger in ART than in control mice (P < 0.001). In line with these morphological differences, neurological performance assessed by the Bederson and RotaRod tests 24 and 48 h after artery occlusion was significantly worse in ART compared with control mice. Plasma levels of TNF-alpha, were also significantly increased in ART vs. control mice after stroke (P < 0.05). As potential underlying mechanisms, we identified increased blood-brain barrier permeability evidenced by increased IgG extravasation associated with decreased tight junctional protein claudin-5 and occludin expression, increased oxidative stress and decreased NO-bioactivity in ART compared with control mice. CONCLUSIONS: In wildtype mice, ART predisposes to significantly worse morphological and functional stroke outcomes, related at least in part to altered blood-brain barrier permeability. These findings demonstrate that ART, by inducing premature vascular aging, not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. TRANSLATIONAL PERSPECTIVE: This study highlights that ART not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. The findings should raise awareness in the ever-growing human ART population in whom these techniques cause similar alterations of the cardiovascular phenotype and encourage early preventive and diagnostic efforts.

Tumour Necrosis Factor-α Inhibition Improves Stroke Outcome in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder where incidence and severity of myocardial infarction are increased. Data on the incidence and outcome of stroke are conflicting. Thus, we investigated outcome after Ischemia/Reperfusion (I/R) brain injury in a mouse model of RA and assessed for the role of the tumour necrosis factor-α (TNF-α) inhibitor Infliximab herein. We used a TNF-α reliant mouse model of RA. RA and wildtype (WT) animals were treated with vehicle (RA/WT) or Infliximab (RA Infliximab) for 4 weeks, before undergoing I/R brain injury. RA-animals displayed larger strokes and poorer neurological performance. Immunohistochemistry on brain sections revealed increased numbers of resident and peripheral innate immune cells (microglia and macrophages); increased Blood-Brain-Barrier (BBB)-disruption; decreased levels of the tight junction proteins (TJPs) claudin-5 and occludin; increased expression of matrix-metalloproteinases (MMP)-3 and -9 and enhanced lipid peroxidation. Treatment with Infliximab corrected these alterations. We show that RA associates to worse stroke-outcome via exacerbated BBB degradation by decrease of the TJPs claudin-5 and occludin. We identified MMPs-3 and -9 and increased oxidative stress as potential mediators thereof. Increased numbers of resident and peripheral innate immune cells (microglia and macrophages) may in turn contribute to all these effects. Infliximab-treatment restored the phenotype of RA-mice to baseline. Our data provide evidence clearly linking RA to adverse stroke-outcome in mice and indicate an approved TNF-α inhibitor as a potential strategy to reduce stroke-burden in this setting.

Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial.

AIM: To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety. METHODS: This randomised, double-blind controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100-200 mg b.d., ibuprofen 600-800 mg t.d.s. or naproxen 375-500 mg b.d. plus esomeprazole, and low-dose aspirin or corticosteroids if already prescribed. Clinically significant GI events (CSGIE-bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia (IDA) were adjudicated blindly. RESULTS: Mean treatment and follow-up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios (HR) were 0.43 (95% CI 0.27-0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32-0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27-0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25-0.62, P < 0.0001) vs naproxen. Even taken with low-dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen (HR 0.52 [0.29-0.94], P = 0.03), and less IDA vs naproxen (0.42 [0.23-0.77, P = 0.005]). Corticosteroid use increased total GI events and CSGIE. H. pylori serological status had no influence. CONCLUSIONS: Arthritis patients taking NSAIDs plus esomeprazole have infrequent clinically significant gastrointestinal events. Co-prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low-dose aspirin or corticosteroids.

Omega-3 fatty acids predict recurrent venous thromboembolism or total mortality in elderly patients with acute venous thromboembolism.

Essentials The role of omega-3 fatty acids (n-3 FAs) in recurrent venous thromboembolism (VTE) is unknown. Association of n-3 FAs with recurrent VTE or total mortality was investigated in 826 patients. Whole blood n-3 FAs were inversely correlated with recurrent VTE or total mortality. Major and non-major bleeding was not increased in patients with higher levels of n-3 FAs. SUMMARY: Background The role of omega-3 fatty acids (n-3 FAs) in recurrent venous thromboembolism (VTE) remains unknown. Objectives To investigate the association of n-3 FAs with recurrent VTE or total mortality at 6 months and 3 years. Methods N-3 FAs were assessed in 826 patients aged ≥ 65 years, categorized into low, medium and high based on the 25th and 75th percentile. Mean follow-up was 29 months. Results At 6 months, subjects with medium (adjusted hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.22-0.62) and high n-3 FA levels (adjusted HR, 0.36; 95% CI, 0.20-0.67) were less likely to develop recurrent VTE or total mortality, compared with those with low n-3 FAs. At 3 years, medium levels (adjusted HR, 0.67; 95% CI, 0.47-0.96) were associated with lower risk of recurrent VTE or total mortality. As compared with low n-3 FAs, the adjusted sub-hazard ratio [SHR] of recurrent VTE was 0.39 (95% CI, 0.15-0.99) in patients with medium and 0.17 (95% CI, 0.03-0.82) in patients with high n-3 FAs. The cumulative incidence of recurrent VTE was lower in the medium and high n-3 FA groups as compared with the low n-3 FA groups, but seems to have worn off after 3 years. The incidence of major and non-major bleeding was not greater in the high n-3 FA group. Conclusion Higher levels of n-3 FAs were associated with a lower risk of recurrent VTE or total mortality in elderly patients with VTE, but not with greater bleeding risk.

Unfavorable Donor Pretransplant APACHE II, SAPS II, and SOFA Scores Are Not Associated With Outcome: Implications for Heart Transplant Donor Selection.

BACKGROUND: The quality of the donor heart and the individual risk of the recipient awaiting heart transplantation are difficult to assess. We investigated whether routinely used intensive care scoring systems can provide additional prognostic information on outcomes after heart transplantation. METHODS: A total of 114 consecutive patients who underwent heart transplantation were included. The Acute Physiology and Chronic Health Evaluation II (APACHE II), the Simplified Acute Physiology Score (SAPS II), and the Sequential Organ Failure Assessment (SOFA) scores were calculated for donors and recipients. Risk factors such as the donor's cause of death, donor's catecholamine use, dialysis status of the recipient, and smoking pattern of the donor and the recipient were assessed. The association of these parameters with mortality, length of stay on the intensive care unit, and need for invasive ventilation was investigated. RESULTS: The median APACHE II score of the donors was 20 (confidence interval [CI], 19-20), the median SAPS II score was 46 (CI, 45-48), and the median SOFA score was 10 (CI, 9-10). In contrast, the median scores of the recipients were as follows: APACHE II, 7 (CI, 6-8); SAPS II, 13 (CI, 12-14); and SOFA, 1 (CI, 1-2). None of the scores as calculated significantly predicted clinical outcome after transplantation. CONCLUSIONS: This study detected no prognostic impact of donor-related risk factors on outcome after heart transplantation. Our findings support the growing practice of also considering organs from donors with high-risk scores for heart transplantation.

Endothelial function and sympathetic nervous system activity in patients with Takotsubo syndrome.

BACKGROUND: Takotsubo syndrome (TTS) is an acute cardiomyopathy associated with intense physical or emotional stress. The precise mechanisms of the disease remain unclear. The aim of this study was to study alterations in endothelial function, vascular compliance and structure and muscle sympathetic activity in the stable phase of the disease. METHODS: In this prospective observational study, patients with TTS and controls matched for age, sex, cardiovascular risk factors and medications were recruited. Flow-mediated vasodilatation (FMD) as a measure of endothelial dysfunction was the primary endpoint. Secondary endpoints included measurements of arterial stiffness, carotid atherosclerosis, quality of life and laboratory parameters. In a subset of patients, muscle sympathetic activity was measured before and after stress tests. RESULTS: The study included 22 TTS patients and 21 matched controls. A significant increase in endothelial dysfunction was seen in TTS compared to controls (FMD 3.4±2.4% vs. 4.8±1.9%, p=0.016). No significant differences in arterial stiffness, intima-media thickness, quality of life and laboratory markers including endothelin-1 were noted. TTS patients showed a reduced carotid total plaque area compared to controls (TPA 17.3±15.1 vs 24.7±12.8mm2, p=0.02). A trend of increased muscle sympathetic activity at rest was observed in TTS patients vs. controls (53.5±28.4 vs. 29.4±16.5 bursts/100 heart beats, p=0.09) with no significant differences in muscle sympathetic activity in response to stress. CONCLUSIONS: Our findings underscore the importance of endothelial dysfunction in patients with TTS which may be involved in the pathophysiology of this syndrome. CLINICALTRIALS. GOV IDENTIFIER: NCT01249599.

Individualized antithrombotic therapy.

UNLABELLED: Clot formation in the circulation is a physiological mechanism preventing bleeding at sites of loss of vascular integrity. Clot formation may also occur intravascularly under pathological conditions, e.g. leading to myocardial infarction, stroke, and critical limb ischaemia. Clot formation involves activation of the coagulation cascade and of platelets eventually leading to an occlusive clot. In the venous circulation, clots are rich in erythrocytes and fibrin, while in the arterial circulation platelets predominate. Accordingly, drugs have been developed to interfere with the activation of the coagulation and/or platelets. As several coagulation factors such as factor VII, VIIII, X and thrombin (factor II) are vitamin K-dependent, drugs interfering with the effects of the vitamin (VKAs), i.e. warfarin, marcoumar or sintrom have been used for decades to prevent thromboembolism and embolic stroke. With the advent of selective inhibitors of factor X (apixaban, edoxaban and rivaroxaban) or factor II (dabigratan) the therapeutic spectrum of anti-thrombotic therapy has been expanded. On the other hand, platelet inhibitors such as aspirin and thienopyridines, i.e. clopidogrel, prasugrel, and ticagrelor have extensively been used to treat arterial disease in the coronary, cerebrovascular and peripheral circulation. Individualized antithrombotic therapy considers (1) characteristics of the disease and (2) those of the patient. Such a decision tree first separates "arterial" and "venous" thrombi. For the prevention of arterial thrombi that occur in acute myocardial infarction and certain forms of stroke and critical limb ischemia, platelet inhibitors are indicated. The first line drug is aspirin which interferes with thromboxane A2 (TXA2) formation and partially inhibits platelet activation. In patients receiving a stent or in acute coronary syndromes (ACS), the combination of aspirin with a thienopyridine is indicated. On the other hand, patients with venous clots should be treated with anticoagulants interfering with the activation of the coagulation cascade. While the longest experiences exist with vitamin K antagonists, the novel oral anticoagulants (NOACs) are at least as effective, but associated with less intracerebral and life-threatening bleeding. VKAs remain the treatment of choice in patients receiving artificial heart valves or with renal failure (in general a GFR of 30 ml/min/KG or less). In the remaining patients, current evidence suggests that NOACs should be preferred. The NOACs are well documented in patients with thromboembolism and atrial fibrillation. Whether patients with an acute ACS should receive dual antiplatelet drugs plus a low dose NOAC is a matter of debate, although conceptually it is an attractive concept. In patients after stent implantation with atrial fibrillation, in which a triple therapy with dual antiplatelet drugs and an anticoagulant is indicated, bleeding is an issue. Recent data suggest that administering a thienopyridine plus warfarin (or possibly a NOAC), while at the same time skipping aspirin may be an alternative to avoid severe bleeding and to maintain antithrombotic efficacy. CONCLUSION: An extensive therapeutic arsenal to interfere with clot formation requires an individualized approach considering the disease condition and co-morbidities of the patient, the anticoagulants' and patient characteristics. This review builds on and extends previous publications of the authors on this topic.

Gender-Related Differences in Patients Presenting with Suspected Acute Coronary Syndromes: Clinical Presentation, Biomarkers and Diagnosis.

OBJECTIVES: Gender differences in patients presenting with suspected acute coronary syndromes (ACS) have not yet been fully characterized. The aim of this study was to assess gender-related disparities in clinical profiles, biomarkers and diagnoses of patients with suspected ACS. METHODS: This single-centre, prospective cohort study included 377 consecutive patients presenting with suspected ACS to the emergency department. Suspected ACS was defined as a request for conventional troponin T (c-cTnT) measurements on clinical grounds. RESULTS: Women were older than men (p = 0.004), and had a lower prevalence of known coronary artery and peripheral vascular disease (p < 0.05). c-cTnT was positive in 8% of female and in 14% of male patients (p = 0.16), TIMI risk score and cardiac biomarkers including c-cTnT, hs-cTnT, myoglobin, creatine kinase, N-terminal pro-brain natriuretic peptide, myeloid-related protein 8/14 and pregnancy-associated plasma protein A were lower in women (p < 0.05). Women were less frequently diagnosed with ACS (30 vs. 51%), and were not referred for urgent coronary angiography as often as men (p < 0.001). In multivariate analysis, female gender was associated with a lower referral for coronary angiography (HR 0.41, 95% CI 0.23-0.78, p = 0.006). CONCLUSIONS: In patients with suspected ACS, women presented with different biomarker profiles, and were less often diagnosed with ACS and referred to coronary angiography.

Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke.

AIM: Constitutive genetic deletion of the adaptor protein p66(Shc) was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66(Shc) gene regulation in human ischaemic stroke. METHODS AND RESULTS: Ischaemia/reperfusion brain injury was induced by performing a transient middle cerebral artery occlusion surgery on wild-type mice. After the ischaemic episode and upon reperfusion, small interfering RNA targeting p66(Shc) was injected intravenously. We observed that post-ischaemic p66(Shc) knockdown preserved blood-brain barrier integrity that resulted in improved stroke outcome, as identified by smaller lesion volumes, decreased neurological deficits, and increased survival. Experiments on primary human brain microvascular endothelial cells demonstrated that silencing of the adaptor protein p66(Shc) preserves claudin-5 protein levels during hypoxia/reoxygenation by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and reactive oxygen species production. Further, we found that in peripheral blood monocytes of acute ischaemic stroke patients p66(Shc) gene expression is transiently increased and that this increase correlates with short-term neurological outcome. CONCLUSION: Post-ischaemic silencing of p66(Shc) upon reperfusion improves stroke outcome in mice while the expression of p66(Shc) gene correlates with short-term outcome in patients with ischaemic stroke.

[Quality and integrity in the production and publication of scientific results: data trimming, manipulation and (self) plagiarism]. / Qualität und Integrität bei der Erstellung und Veröffentlichung wissenschaftlicher Ergebnisse: Daten-Trimming, -manipulation, und (Auto-)Plagiate.

The publication of scientific manuscripts is an essential part in the research process and in the attempt to produce novel knowledge: only what is published exists. It is the aim of research to produce reproducible and sustainable knowledge. Reproducible knowledge is based on precise observation, the use of modern methodologies and an appropriate statistical analysis. As a consequence, it must be the intention of any scientist to report the truth and nothing but the truth. This principle requires precision and honesty. Deviation from such a behavior may lead to scientific misconduct: It encompasses the use of inappropriate methods and/or statistics, double publication of data, sloppy data presentation and processing, up to data massaging, manipulation, data theft or fabrication. Famous examples can be found throughout the history of research but it appears that such behavior has recently become more common possibly due to excessive competition, the crucial role of grants for scientific productivity and funding as well as promotion. Accordingly, in the training of researchers it seems essential to emphasize the importance of precise data acquisition and analysis to ascertain reproducible data. Similarly, it must be assured that data sets are only published once, that authors have contributed technically and/or intellectually in an important manner and that the work of other scientists is cited appropriately. Editors and reviewers should carefully assess the quality of submitted manuscripts. In fact, it is the aim of the peer review process to assure as much as possible that the quality of submitted manuscripts meets current methodological as well as ethical standards.

Vitamin K antagonists. Ready to be replaced?

For the last decades, anticoagulation for stroke prevention in atrial fibrillation (AF) as well as for the prophylaxis and long-term treatment of venous thromboembolism has been entirely based on vitamin K antagonists (VKA). Although very effective under optimal conditions, long-term treatment with these drugs is flawed by the fact that the time in the therapeutic range frequently is suboptimal due to biological factors, drug interactions and compliance. The direct thrombin inhibitor dabigatran, as well as the direct FXa inhibitors rivaroxaban and apixaban provide more consistent anticoagulation and have proven their efficacy and safety against VKAs in several large scale randomized clinical trials for stroke prevention in atrial fibrillation as well as for the treatment and prevention of venous thromboembolism. In view of these convincing data and other advantages such as the lack of mandatory monitoring and only few drug interactions, VKAs will most likely be replaced in a majority of patients for these indications. Based on the most recent trial evidence, the current review discusses the role of VKA treatment and that of the novel anticoagulants.

Coronary computed tomography angiography indicates complexity of percutaneous coronary interventions.

BACKGROUND: Coronary computed tomography angiography (CCTA) provides information regarding lesion morphology and three-dimensional coronary anatomy incremental to coronary angiography. We addressed the question whether preprocedural CCTA bears potential for guiding percutaneous coronary interventions (PCI). METHODS AND RESULTS: Sixty-six coronary lesions attempted with PCI within 6 months of preprocedural CCTA were retrospectively assessed. Lesion parameters from unenhanced computed tomography (CT) for calcium scoring and CCTA were analyzed and compared with PCI complexity. Complex PCI was defined as use of buddy wire, kissing balloon, necessity of high pressure balloons, or rotablator. Complex PCIs were observed in 32 interventions (48%). Median Agatston score and Hounsfield units were higher in lesions with complex as compared to those with non-complex interventions with 130 (interquartile range, 23-276) vs 29 (0-158; P=.01), and 493 (245-631) vs 341 (68-520 Hounsfield Units; P=.04), respectively. Median local plaque volume and plaque mass were higher in complex PCI with 17 (2-39) vs 5 (0-19.5 mm³; P=.007), and 48 (15-99) vs. 16 (1.5-63 mg hydroxyapatite/mm³; P=.03), respectively. Lesions leading to complex PCI were longer [1.8 (1.2-2.8) vs 1.3 (0.8-1.7) cm; P=.03], and had a higher rate of calcified plaques (23% vs 3%; P=.03). There was a significant correlation between CCTA- and angiography-derived local SYNTAX Scores (P<.001); the CCTA-derived score seems to be predictive for failed and complex PCI (area under curve = 0.75 ± 0.13 and 0.66 ± 0.08, respectively). CONCLUSIONS: Preprocedural lesion assessment by CCTA indicates complexity of PCI. In patients with suspected complex coronary anatomy, prior CCTA adds important information for planning PCI.

[Stem and progenitor cell-based therapy approaches: current developments on treatment of acute myocardial infarction and chronic ischemic cardiomyopathy]. / Stamm- und progenitorzellbasierte Therapieansätze : Aktuelle Entwicklungen zur Behandlung des akuten Myokardinfarkts und der chronischen ischämischen Kardiomyopathie.

Percutaneous coronary intervention (PCI) for coronary revascularization in conjunction with an optimized pharmacological treatment can reduce adverse left ventricular remodeling and dysfunction in patients with acute myocardial infarction. Despite these modern therapeutic strategies a significant number of these patients continue to develop adverse cardiac remodeling and LV dysfunction which is associated with a poor prognosis. Stem and progenitor cell-based approaches for treatment of acute myocardial infarction and chronic ischemic cardiomyopathy are an interesting direction of current experimental and clinical research. The current review article provides a summary of recent developments of cell-based therapies of ischemic heart disease, including the assessment of the repair and regeneration capacity of different stem and progenitor cell populations. In addition the advantages and disadvantages of different modes of cell application and potential strategies for the improvement of stem and progenitor cell function for their use in cell-based cardiovascular therapies will be described.

CYP4A11 polymorphism correlates with coronary endothelial dysfunction in patients with coronary artery disease--the ENCORE Trials.

BACKGROUND: Cytochrome P450 (CYP) is expressed in the human endothelium and metabolizes arachidonic acid into vasoactive epoxyeicosatrienoic and 20-hydroxyeicosatetraenoic acids. CYP enzymes have been linked to hypertension and generation of reactive oxygen species. Thus, we investigated the impact of several CYP polymorphisms on coronary endothelial function in patients with coronary artery disease (CAD). METHODS AND RESULTS: We determined CYP4A11 F434S, CYP2C9 I359L, CYP2C9 G144C and CYP 2J2 promotor -50G>T polymorphisms in 734 patients with CAD undergoing percutaneous coronary intervention. Increasing concentrations of acetylcholine were infused in a coronary segment without angiographically significant CAD and the coronary artery vasomotor response was measured by quantitative angiography. Patients with substitution of phenylalanine 434 by serine (434SS, n=15, 2.04%) in CYP4A11 F434 demonstrated significantly augmented endothelium-dependent vasoconstriction (p=0.044 after Bonferroni correction) compared to patients with the 434FS (n=193, 26.29%) and 434FF genotype (n=526, 71.66%) before and after adjustment for blood pressure and HDL-cholesterol. In addition, patients with the 434SS genotype had higher systolic blood pressure levels (p=0.039) compared to the two other groups. The CYP 2C9 and CYP 2J2 polymorphisms did not show any correlation with coronary vasoconstriction, hypertension, diabetes mellitus, blood pressure or cholesterol. CONCLUSION: In patients with established and stable coronary artery disease the 434SS variant of CYP4A11 F434 is associated with pronounced coronary vasoconstriction.

Physician compliance with advanced electronic alerts for preventing venous thromboembolism among hospitalized medical patients.

BACKGROUND: Worldwide, more than half of the hospitalized medical patients at high risk do not receive venous thromboembolism (VTE) prophylaxis. Although VTE among hospitalized patients at risk is reduced with electronic alerts (eAlerts), the majority of eAlerts are being ignored by the responsible physician. METHODS: We investigated physician compliance with an advanced eAlert system in 1027 (age 59 +/- 17 years) hospitalized medical patients. A continuously flashing non-interruptive eAlert, visible to all healthcare professionals, was issued in the electronic patient chart 6 h after admission if the physician did not order prophylaxis. RESULTS: The rate of appropriate prophylaxis increased from 44% before to 76% after the implementation of the eAlert system. Although the patients whose physicians cared for > or = 20 patients during the study period had a more frequent physician response to the eAlert than patients whose physicians cared for fewer patients (69% vs. 40%, P < 0.001), they received appropriate prophylaxis less often (72% vs. 81%, P = 0.016). After adjustment for significant patient predictors of appropriate prophylaxis, including cancer, age, duration of hospital stay, and thrombocytopenia, patients whose physicians cared for > or = 20 patients during the study period were less likely to receive appropriate prophylaxis (odds ratio 0.65, 95% confidence interval 0.44-0.96; P = 0.032) than patients whose physicians cared for fewer patients. CONCLUSIONS: The introduction of an advanced eAlert system accompanied by continuing medical education for the prevention of VTE resulted in a substantial increase in the rate of appropriate prophylaxis among hospitalized medical patients. However, many eAlerts may cause decreased physician compliance owing to 'alert fatigue'.