Cardiovascular Evaluation of Etrasimod, a Selective Sphingosine 1-phosphate Receptor Modulator, in Healthy Adults: Results of a Randomized, Thorough QT/QTc Study.

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator used as an oral treatment option for immune-mediated inflammatory disorders. This randomized, double-blind, placebo- and positive-controlled, parallel-group, healthy adult study investigated etrasimod's effect on the QT interval and other electrocardiogram parameters. All participants received etrasimod-matched placebo on day 1. Group A received once-daily, multiple ascending doses of etrasimod (2-4 mg) on days 1-14 and moxifloxacin-matched placebo on days 1 and 15. Group B received etrasimod-matched placebo on days 1-14 and either moxifloxacin 400 mg or moxifloxacin-matched placebo on days 1 and 15. The primary analysis was a concentration-QTc analysis using a corrected QT interval by Fridericia (QTcF). The etrasimod concentration-QTc analysis predicted placebo-corrected change from baseline QTcF (ΔΔQTcF) values and associated 90% confidence intervals remained <10 milliseconds over the observed etrasimod plasma concentration range (≤279 ng/mL). Etrasimod was associated with mild, transient, asymptomatic heart rate slowing that was most pronounced on day 1 (2 mg, first dose). The largest-by-time point mean placebo-corrected changes in heart rate from time-matched day -1 baseline (∆∆HR) on days 1, 7 (2 mg, last dose), and 14 (4 mg, last dose) were -15.1, -8.5, and -6.0 bpm, respectively. Etrasimod's effects on PR interval were small, with the largest least squares mean placebo-corrected change from baseline in PR interval (∆∆PR) being 6.6 milliseconds. No episodes of atrioventricular block were observed. Thus, multiple ascending doses of etrasimod were not associated with clinically relevant QT/QTc effects in healthy adults and only had a mild, transient, and asymptomatic impact on heart rate.

Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study.

BACKGROUND AND AIMS: Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks. METHODS: In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks. RESULTS: In all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients. CONCLUSIONS: In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment.

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers.

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0-1.5 h post-dose and mean terminal elimination half-life values from 20.5-26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34-4.49 (QD dosing) and 1.95-2.36 (BID dosing). Mean effective half-life values ranged from 17.5-18.4 h, reflecting ∼1.7-fold (QD dosing) and ∼2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate-release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.

Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). METHODS: In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint. RESULTS: At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30-1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure. CONCLUSIONS: In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302.

Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial.

PURPOSE: This phase 2 study was designed to assess the efficacy, safety and tolerability of immediate-release orally administered ralinepag, a selective, non-prostanoid prostacyclin receptor agonist with a 24-h terminal half-life, compared to placebo in adult patients with symptomatic pulmonary arterial hypertension (PAH). METHODS: 61 PAH patients who were receiving standard care, including mono or dual PAH-targeted background therapy were randomised 2:1 to ralinepag (n=40) or placebo (n=21). The starting dose of ralinepag was 10 µg twice daily. Dosage was then up-titrated as tolerated over the course of the 9-week dose-titration period, to a maximum total daily dose of 600 µg (300 µg twice daily). The primary efficacy end-point was the absolute change in pulmonary vascular resistance (PVR) from baseline to week 22. Additional end-points included percentage change in PVR from baseline, other haemodynamic parameters, 6-min walk distance (6MWD) and safety and tolerability. RESULTS: Ralinepag significantly decreased PVR by 163.9 dyn·s·cm-5 compared to an increase of 0.7 dyn·s·cm-5 with placebo (p=0.02); the least-squares mean change from baseline PVR was -29.8% compared with placebo (p=0.03). 6MWD increased from baseline by 36.2 m with ralinepag and 29.4 m with placebo (p=0.90). Serious adverse events occurred in 10% of ralinepag patients and 29% of placebo patients. Study discontinuations occurred in 13% of ralinepag patients and 10% of placebo patients. SUMMARY: Ralinepag reduced PVR compared with placebo in PAH patients on mono (41%) or dual combination (59%) background therapy.

Recent developments in the science of proarrhythmic cardiac safety of new drugs.

Following marketing withdrawals of several drugs due to proarrhythmic safety concerns, the ICH Guidelines S7B and E14 were released in 2005 and have guided pre-approval cardiac safety assessments in multiple regulatory jurisdictions. While this S7B-E14 paradigm has successfully prevented drugs with unanticipated potential for inducing Torsades de Pointes entering the market, it has unintentionally resulted in the termination of development programs for potentially important compounds that could have exhibited a favourable benefit-risk balance. The Comprehensive In vitro Proarrhythmia Assay paradigm is currently attracting considerable attention as a solution to this problem. While much evaluative work in this new paradigm will be conducted in the non-clinical domain, human electrocardiographic assessments will remain an important component of the overall investigational strategy, possibly being conducted in Phase I trials employing exposure-response modelling. This article reviews recent developments in proarrhythmic cardiac safety assessments of new drugs, their rationales, and current limitations.

The Cardiac Safety Research Consortium enters its second decade: An invitation to participate.

The Cardiac Safety Research Consortium (CSRC), a transparent, public-private partnership established in 2005 as a Critical Path Program and formalized in 2006 under a Memorandum of Understanding between the United States Food and Drug Administration and Duke University, is entering its second decade. Our continuing goal is to advance paradigms for more efficient regulatory science related to the cardiovascular safety of new therapeutics, both in the United States and globally, particularly where such safety questions add burden to innovative research and development. Operationally, CSRC brings together a broad base of stakeholders from academia, industry, and government agencies in a collaborative forum focused on identifying barriers and then creating novel solutions through shared data, expertise, and collaborative research. This white paper provides a brief overview of the Consortium's activities in its first decade and a context for some of our current activities and future directions. The growth and success of the CSRC have been primarily driven by members' active participation and the development of goodwill and trust throughout our membership, which have facilitated novel collaborations across traditionally competitive or contentious stakeholder boundaries. The continued expansion of our base of participating academicians, industry experts, and regulators will define the Consortium's success in our second decade. It is our hope that sharing our endeavors to date will stimulate additional participation in the CSRC and also provide a model for other groups starting to develop similar collaborative forums.

Cardiovascular safety monitoring during oncology drug development and therapy.

Assessments of cardiac and cardiovascular toxicity are prominent components of drug safety endeavors during drug development and clinical practice. Oncologic drugs bring several challenges to both domains. First, during drug development, it is necessary to adapt the ICH E14 "Thorough QT/QTc Study" because the cytotoxic nature of many oncologics precludes their being administered to healthy individuals. Second, appropriate benefit-risk assessments must be made by regulators: given the benefit these drugs provide in life-threatening illnesses, a greater degree of risk may be acceptable when granting marketing authorization than for drugs for less severe indications. Third, considerable clinical consideration is needed for patients who are receiving and have finished receiving pharmacotherapy. Paradoxically, although such therapy has proved very successful in many cases, with disease states going into remission and patients living for many years after cessation of treatment, cardiotoxicities can manifest themselves relatively soon or up to a decade later. Oncologic drugs have been associated with various off-target cardiovascular responses, including cardiomyopathy leading to heart failure, cardiac dysrhythmias, thromboembolic events, and hypertension. Follow-up attention and care are, therefore, critical. This article reviews the process of benefit-risk estimation, provides an overview of nonclinical and preapproval clinical assessment of cardiovascular safety of oncology drugs, and discusses strategies for monitoring and management of patients receiving drugs with known cardiotoxicity risk. These measures include cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogs and cardioprotectants, and early detection of myocardial cell injury using biomarkers.

Impact of ABCB1 allelic variants on QTc interval prolongation.

PURPOSE: Although the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e., blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT prolongation and cardiotoxicity. EXPERIMENTAL DESIGN: ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (-/-) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced heart rate-corrected QT interval (QTc) prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. RESULTS: Here, we show that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT prolongation from baseline (ΔQTc) over time. Consistent with this observation, we also show that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ΔQTc following a single dose of romidepsin. CONCLUSIONS: To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT prolongation following the administration of ABCB1-substrate drugs.

Daptomycin compared to standard therapy for the treatment of native valve endocarditis

Introduction In a recent randomized trial of Staphylococcus aureus bacteremia and native valve endocarditis, daptomycin was found not inferior to standard therapy. We summarized findings in the subgroup of patients with endocarditis according to the Duke criteria. Methods Patients were randomly assigned to receive daptomycin 6mg/kg/day or standard therapy (vancomycin 1g every 12h or antistaphylococcal penicillin 2g every 4h, both with gentamicin 1mg/kg every 8h for the first 4 days). The primary end point was success in the modified intent-to-treat population 6 weeks after the end of therapy.Results Fifty-three patients were included: 35 with right-sided endocarditis (RIE) and 18 with left-sided endocarditis (LIE). The success rates in patients with RIE were similar between daptomycin and the comparator (42% vs 44%). Patients with RIE with septic pulmonary infarcts responded similarly to treatment with daptomycin and standard therapy (60% vs 67%). In the LIE population, treatment success rates were poor in both arms (11% vs 22%).Conclusion Daptomycin is an efficacious and well-tolerated alternative to standard therapy in the treatment of RIE. Patients with LIE had a poor outcome regardless of the treatment received. Daptomycin is also effective in treating endocarditis with septic pulmonary infarcts (AU)

Introducción En un reciente ensayo aleatorizado sobre bacteriemia por Staphylococcus aureus y endocarditis de la válvula natural, daptomicina no resultó inferior a la terapéutica estándar. Resumimos los hallazgos en el subgrupo de pacientes con endocarditis según los criterios de Duke.MétodosLos pacientes fueron asignados aleatoriamente a recibir daptomicina, 6mg/kg/día, o la terapéutica estándar (vancomicina 1g cada 12h o una penicilina antiestafilocócica 2g cada 4h, ambos con gentamicina 1mg/kg cada 8h, durante los 4 primeros días). La variable principal fue el éxito en la población modificada por intención de tratamiento 6 semanas después del final del tratamiento.Resultados El estudio incluyó a 53 pacientes: 35 con endocarditis infecciosa de las cavidades derechas (RIE) y 18 con endocarditis infecciosa de las cavidades izquierdas (LIE). En los pacientes con RIE, las tasas de éxito con daptomicina y el tratamiento de comparación fueron similares (42% frente a 44%). Los pacientes con RIE e infartos pulmonares sépticos respondieron de forma similar al tratamiento con daptomicina y con la terapéutica estándar (60% frente a 67%). En la población con LIE, las tasas de éxito fueron pobres con ambos brazos (11% frente a 22%).Conclusión Daptomicina es una alternativa eficaz y bien tolerada a la terapéutica estándar en el tratamiento de la RIE. Los pacientes con LIE tuvieron mal resultado, con independencia del tratamiento recibido. Daptomicina también es eficaz en el tratamiento de la endocarditis con infartos pulmonares sépticos (AU)

Daptomycin compared to standard therapy for the treatment of native valve endocarditis.

INTRODUCTION: In a recent randomized trial of Staphylococcus aureus bacteremia and native valve endocarditis, daptomycin was found not inferior to standard therapy. We summarized findings in the subgroup of patients with endocarditis according to the Duke criteria. METHODS: Patients were randomly assigned to receive daptomycin 6 mg/kg/day or standard therapy (vancomycin 1g every 12h or antistaphylococcal penicillin 2g every 4h, both with gentamicin 1mg/kg every 8h for the first 4 days). The primary end point was success in the modified intent-to-treat population 6 weeks after the end of therapy. RESULTS: Fifty-three patients were included: 35 with right-sided endocarditis (RIE) and 18 with left-sided endocarditis (LIE). The success rates in patients with RIE were similar between daptomycin and the comparator (42% vs 44%). Patients with RIE with septic pulmonary infarcts responded similarly to treatment with daptomycin and standard therapy (60% vs 67%). In the LIE population, treatment success rates were poor in both arms (11% vs 22%). CONCLUSION: Daptomycin is an efficacious and well-tolerated alternative to standard therapy in the treatment of RIE. Patients with LIE had a poor outcome regardless of the treatment received. Daptomycin is also effective in treating endocarditis with septic pulmonary infarcts.

Analysis of the impact of early surgery on in-hospital mortality of native valve endocarditis: use of propensity score and instrumental variable methods to adjust for treatment-selection bias.

BACKGROUND: The impact of early surgery on mortality in patients with native valve endocarditis (NVE) is unresolved. This study sought to evaluate valve surgery compared with medical therapy for NVE and to identify characteristics of patients who are most likely to benefit from early surgery. METHODS AND RESULTS: Using a prospective, multinational cohort of patients with definite NVE, the effect of early surgery on in-hospital mortality was assessed by propensity-based matching adjustment for survivor bias and by instrumental variable analysis. Patients were stratified by propensity quintile, paravalvular complications, valve perforation, systemic embolization, stroke, Staphylococcus aureus infection, and congestive heart failure. Of the 1552 patients with NVE, 720 (46%) underwent early surgery and 832 (54%) were treated with medical therapy. Compared with medical therapy, early surgery was associated with a significant reduction in mortality in the overall cohort (12.1% [87/720] versus 20.7% [172/832]) and after propensity-based matching and adjustment for survivor bias (absolute risk reduction [ARR] -5.9%, P<0.001). With a combined instrument, the instrumental-variable-adjusted ARR in mortality associated with early surgery was -11.2% (P<0.001). In subgroup analysis, surgery was found to confer a survival benefit compared with medical therapy among patients with a higher propensity for surgery (ARR -10.9% for quintiles 4 and 5, P=0.002) and those with paravalvular complications (ARR -17.3%, P<0.001), systemic embolization (ARR -12.9%, P=0.002), S aureus NVE (ARR -20.1%, P<0.001), and stroke (ARR -13%, P=0.02) but not those with valve perforation or congestive heart failure. CONCLUSIONS: Early surgery for NVE is associated with an in-hospital mortality benefit compared with medical therapy alone.

Health care-associated native valve endocarditis: importance of non-nosocomial acquisition.

BACKGROUND: The clinical profile and outcome of nosocomial and non-nosocomial health care-associated native valve endocarditis are not well defined. OBJECTIVE: To compare the characteristics and outcomes of community-associated and nosocomial and non-nosocomial health care-associated native valve endocarditis. DESIGN: Prospective cohort study. SETTING: 61 hospitals in 28 countries. PATIENTS: Patients with definite native valve endocarditis and no history of injection drug use who were enrolled in the ICE-PCS (International Collaboration on Endocarditis Prospective Cohort Study) from June 2000 to August 2005. MEASUREMENTS: Clinical and echocardiographic findings, microbiology, complications, and mortality. RESULTS: Health care-associated native valve endocarditis was present in 557 (34%) of 1622 patients (303 with nosocomial infection [54%] and 254 with non-nosocomial infection [46%]). Staphylococcus aureus was the most common cause of health care-associated infection (nosocomial, 47%; non-nosocomial, 42%; P = 0.30); a high proportion of patients had methicillin-resistant S. aureus (nosocomial, 57%; non-nosocomial, 41%; P = 0.014). Fewer patients with health care-associated native valve endocarditis had cardiac surgery (41% vs. 51% of community-associated cases; P < 0.001), but more of the former patients died (25% vs. 13%; P < 0.001). Multivariable analysis confirmed greater mortality associated with health care-associated native valve endocarditis (incidence risk ratio, 1.28 [95% CI, 1.02 to 1.59]). LIMITATIONS: Patients were treated at hospitals with cardiac surgery programs. The results may not be generalizable to patients receiving care in other types of facilities or to those with prosthetic valves or past injection drug use. CONCLUSION: More than one third of cases of native valve endocarditis in non-injection drug users involve contact with health care, and non-nosocomial infection is common, especially in the United States. Clinicians should recognize that outpatients with extensive out-of-hospital health care contacts who develop endocarditis have clinical characteristics and outcomes similar to those of patients with nosocomial infection. PRIMARY FUNDING SOURCE: None.

Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.

BACKGROUND: We sought to provide a contemporary picture of the presentation, etiology, and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide. METHODS: Prospective cohort study of 2781 adults with definite IE who were admitted to 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. RESULTS: The median age of the cohort was 57.9 (interquartile range, 43.2-71.8) years, and 72.1% had native valve IE. Most patients (77.0%) presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health care exposure was found in one-quarter of patients. Staphylococcus aureus was the most common pathogen (31.2%). The mitral (41.1%) and aortic (37.6%) valves were infected most commonly. The following complications were common: stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality remained high (17.7%). Prosthetic valve involvement (odds ratio, 1.47; 95% confidence interval, 1.13-1.90), increasing age (1.30; 1.17-1.46 per 10-year interval), pulmonary edema (1.79; 1.39-2.30), S aureus infection (1.54; 1.14-2.08), coagulase-negative staphylococcal infection (1.50; 1.07-2.10), mitral valve vegetation (1.34; 1.06-1.68), and paravalvular complications (2.25; 1.64-3.09) were associated with an increased risk of in-hospital death, whereas viridans streptococcal infection (0.52; 0.33-0.81) and surgery (0.61; 0.44-0.83) were associated with a decreased risk. CONCLUSIONS: In the early 21st century, IE is more often an acute disease, characterized by a high rate of S aureus infection. Mortality remains relatively high.

Current features of infective endocarditis in elderly patients: results of the International Collaboration on Endocarditis Prospective Cohort Study.

BACKGROUND: Elderly patients are emerging as a population at high risk for infective endocarditis (IE). However, adequately sized prospective studies on the features of IE in elderly patients are lacking. METHODS: In this multinational, prospective, observational cohort study within the International Collaboration on Endocarditis, 2759 consecutive patients were enrolled from June 15, 2000, to December 1, 2005; 1056 patients with IE 65 years or older were compared with 1703 patients younger than 65 years. Risk factors, predisposing conditions, origin, clinical features, course, and outcome of IE were comprehensively analyzed. RESULTS: Elderly patients reported more frequently a hospitalization or an invasive procedure before IE onset. Diabetes mellitus and genitourinary and gastrointestinal cancer were the major predisposing conditions. Blood culture yield was higher among elderly patients with IE. The leading causative organism was Staphylococcus aureus, with a higher rate of methicillin resistance. Streptococcus bovis and enterococci were also significantly more prevalent. The clinical presentation of elderly patients with IE was remarkable for lower rates of embolism, immune-mediated phenomena, or septic complications. At both echocardiography and surgery, fewer vegetations and more abscesses were found, and the gain in the diagnostic yield of transesophageal echocardiography was significantly larger. Significantly fewer elderly patients underwent cardiac surgery (38.9% vs 53.5%; P < .001). Elderly patients with IE showed a higher rate of in-hospital death (24.9% vs 12.8%; P < .001), and age older than 65 years was an independent predictor of mortality. CONCLUSIONS: In this large prospective study, increasing age emerges as a major determinant of the clinical characteristics of IE. Lower rates of surgical treatment and high mortality are the most prominent features of elderly patients with IE. Efforts should be made to prevent health care-associated acquisition and improve outcomes in this major subgroup of patients with IE.

Phylogenetic analysis of viridans group streptococci causing endocarditis.

Identification of viridans group streptococci (VGS) to the species level is difficult because VGS exchange genetic material. We performed multilocus DNA target sequencing to assess phylogenetic concordance of VGS for a well-defined clinical syndrome. The hierarchy of sequence data was often discordant, underscoring the importance of establishing biological relevance for finer phylogenetic distinctions.

Relation of troponin elevation to outcome in patients with infective endocarditis.

Elevated troponin is increasingly recognized as a marker of cardiac injury and poor outcomes in diverse disease states. It was hypothesized that patients with infective endocarditis (IE) and elevated cardiac troponin would have more extensive IE and worse clinical outcomes. Patients were enrolled as part of the International Collaboration on Endocarditis (ICE) prospective cohort study; analysis of these patients was done retrospectively. Data from 83 consecutively enrolled patients from a single center were evaluated. Cardiac troponin I (cTnI) was drawn for clinical indications and before any cardiac surgery in 51 of the 83 patients. Outcomes evaluated were hospital mortality, annular or myocardial abscess on the basis of echocardiography or surgery, and central nervous system events. Of 51 patients with cTnI drawn, 33 (65%) had elevated cTnI > or =0.1 mg/dl. There were no differences in age, gender, prosthetic valve IE, Staphylococcus aureus IE, or history of coronary artery disease, congestive heart failure, or diabetes mellitus between patients with and without cTnI elevations. Patients with elevated cTnI were less likely to have isolated right-sided IE and more likely to have left ventricular systolic dysfunction or renal dysfunction (p <0.05 for each). In conclusion, elevated cTnI was associated with the composite of death, abscess, and central nervous system events (p <0.001).

Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group.

BACKGROUND: The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for the prevention of infective endocarditis, which were last published in 1997. METHODS: and RESULTS: A writing group appointed by the AHA for their expertise in prevention and treatment of infective endocarditis (IE) with liaison members representing the American Dental Association, the Infectious Diseases Society of America and the American Academy of Pediatrics. The writing group reviewed input from national and international experts on IE. The recommendations in this document reflect analyses of relevant literature regarding procedure-related bacteremia and IE; in vitro susceptibility data of the most common microorganisms, which cause IE; results of prophylactic studies in animal models of experimental endocarditis; and retrospective and prospective studies of prevention of IE. MEDLINE database searches from 1950 through 2006 were done for English language articles using the following search terms: endocarditis, infective endocarditis, prophylaxis, prevention, antibiotic, antimicrobial, pathogens, organisms, dental, gastrointestinal, genitourinary, streptococcus, enterococcus, staphylococcus, respiratory, dental surgery, pathogenesis, vaccine, immunization and bacteremia. The reference lists of the identified articles were also searched. The writing group also searched the AHA online library. The American College of Cardiology/AHA classification of recommendations and levels of evidence for practice guidelines were used. The article subsequently was reviewed by outside experts not affiliated with the writing group and by the AHA Science Advisory and Coordinating Committee. CONCLUSIONS: The major changes in the updated recommendations include the following. (1) The committee concluded that only an extremely small number of cases of IE might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100 percent effective. (2) IE prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE. (3) For patients with these underlying cardiac conditions, prophylaxis is recommended for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. (4) Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of IE. (5) Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. These changes are intended to define more clearly when IE prophylaxis is or is not recommended and to provide more uniform and consistent global recommendations.

Emergence of coagulase-negative staphylococci as a cause of native valve endocarditis.

BACKGROUND: Coagulase-negative staphylococci (CoNS) are an infrequent cause of native valve endocarditis (NVE), and our understanding of NVE caused by CoNS is incomplete. METHOD: The International Collaboration on Endocarditis-Prospective Cohort Study includes patients with endocarditis from 61 centers in 28 countries. Patients with definite cases of NVE caused by CoNS who were enrolled during the period June 2000-August 2006 were compared with patients with definite cases of NVE caused by Staphylococcus aureus and patients with NVE caused by viridans group streptococci. Multivariable logistic regression was used to determine factors associated with death in patients with NVE caused by CoNS. RESULTS: Of 1635 patients with definite NVE and no history of injection drug use, 128 (7.8%) had NVE due to CoNS. Health care-associated infection occurred in 63 patients (49%) with NVE caused by CoNS. Comorbidities, long-term intravascular catheter use, and history of recent invasive procedures were similar among patients with NVE caused by CoNS and among patients with NVE caused by S. aureus. Surgical treatment for endocarditis occurred more frequently in patients with NVE due to CoNS (76 patients [60%]) than in patients with NVE due to S. aureus (150 [33%]; P=.01) or in patients with NVE due to viridans group streptococci (149 [44%]; P=.01). Despite the high rate of surgical procedures among patients with NVE due to CoNS, the mortality rates among patients with NVE due to CoNS and among patients with NVE due to S. aureus were similar (32 patients [25%] and 124 patients [27%], respectively; P=.44); the mortality rate among patients with NVE due to CoNS was higher than that among patients with NVE due to viridans group streptococci (24 [7.0%]; P=.01). Persistent bacteremia (odds ratio, 2.65; 95% confidence interval, 1.08-6.51), congestive heart failure (odds ratio, 3.35; 95% confidence interval, 1.57-7.12), and chronic illness (odds ratio, 2.86; 95% confidence interval, 1.34-6.06) were independently associated with death in patients with NVE due to CoNS (c index, 0.73). CONCLUSIONS: CoNS have emerged as an important cause of NVE in both community and health care settings. Despite high rates of surgical therapy, NVE caused by CoNS is associated with poor outcomes.

Venous thrombosis in patients with short- and long-term central venous catheter-associated Staphylococcus aureus bacteremia.

OBJECTIVE: Infection and thrombosis are important complications of intravascular catheters. The purpose of this study was to determine the incidence of thrombosis in patients with central venous catheter-associated Staphylococcus aureus bacteremia and the utility of physical examination for diagnosing upper extremity or neck venous thrombosis. DESIGN: Prospective observational cohort. SETTING: Tertiary care facility. PATIENTS: In all, 65 consecutive patients with catheter-associated S. aureus bacteremia with central venous catheters of the internal jugular, brachial, or subclavian veins were eligible for participation. INTERVENTION: From July 1999 through August 2004, enrolled patients underwent physical examination and ultrasonography independently to identify the presence of catheter-associated thrombosis. Study ultrasonograms were interpreted blindly using defined criteria. Outcomes were defined at 12-wk follow-up. MEASUREMENTS AND MAIN RESULTS: A total of 48 patients were enrolled. By ultrasonography, definite or possible thrombosis was present in 34 of 48 patients (71%) in this cohort. Death or recurrent bacteremia occurred in 11/34 (32%) infected patients with thrombosis and two of 14 (14%) infected patients without thrombosis (p = .29). Sensitivity of all physical examination findings, either alone or in combination, was low (< or = 24%). Only engorged veins upon hand elevation and the presence of multiple physical examination abnormalities were specific (100% each). CONCLUSIONS: Thrombosis is a common complication of central venous catheter-associated S. aureus bacteremia. Patients with central venous catheter-associated S. aureus bacteremia should undergo ultrasonography to detect thromboses even if the physical examination is normal.