Computerized clinical decision support to improve stroke prevention therapy in primary care management of atrial fibrillation: a cluster randomized trial.

BACKGROUND: Despite guidelines supporting antithrombotic therapy use in atrial fibrillation (AF), under-prescribing persists. We assessed whether computerized clinical decision support (CDS) would enable guideline-based antithrombotic therapy for AF patients in primary care. METHODS: This cluster randomized trial of CDS versus usual care (UC) recruited participants from primary care practices across Nova Scotia, following them for 12 months. The CDS tool calculated bleeding and stroke risk scores and provided recommendations for using oral anticoagulants (OAC) per Canadian guidelines. RESULTS: From June 14, 2014 to December 15, 2016, 203 primary care providers (99 UC, 104 CDS) with access to high-speed Internet were recruited, enrolling 1,145 eligible patients (543 UC, 590 CDS) assigned to the same treatment arm as their provider. Patient mean age was 72.3 years; most were male (350, 64.5% UC, 351, 59.5% CDS) and from a rural area (298, 54.9% UC, 315, 53.4% CDS). At baseline, a higher than anticipated proportion of patients were receiving guideline-based OAC therapy (373, 68.7% UC, 442, 74.9% CDS; relative risk [RR] 0.97 (95% confidence interval [CI], 0.87-1.07; P = .511)). At 12 months, prescription data were available for 538 usual care and 570 CDS patients, and significantly more CDS patients were managed according to guidelines (415, 77.1% UC, 479, 84.0% CDS; RR 1.08 (95% CI, 1.01-1.15; P = .024)). CONCLUSION: Notwithstanding high baseline rates, primary care provider access to the CDS over 12 months further optimized the prescribing of OAC therapy per national guidelines to AF patients potentially eligible to receive it. This suggests that CDS can be effective in improving clinical process of care. TRIAL REGISTRATION: Clinical Trials NCT01927367. https://clinicaltrials.gov/ct2/show/NCT01927367?term=NCT01927367&draw=2&rank=1.

Resource use and cost associated with computerized decision support system and usual care in managing patients with atrial fibrillation: analysis of IMPACT-AF randomized trial data.

BACKGROUND: IMPACT-AF is a prospective, randomized, cluster design trial comparing atrial fibrillation (AF) management with a computerized decision support system (CDS) to usual care (control) in the primary care setting of Nova Scotia, Canada. The objective of this analysis was to compare the resource use and costs between CDS and usual care groups. METHODS: Case costing data, 12-month self-administered questionnaires, and monthly diaries from IMPACT-AF were used in this analysis. Descriptive statistics were used to compare costs and resource use between groups. All costs are presented in 2021 Canadian dollars and cover the 12-month period of participation in the study. RESULTS: A total of 1,145 patients enrolled in the trial. Case costing data were available for 466 participants (41.1%), 12-month self-administered questionnaire data for 635 participants (56.0%) and monthly diary data for 223 participants (19.7%). Emergency department visits and hospitalizations comprised the most expensive component of AF care. Across all three datasets, there were no statistically significant differences in costs or resource use between CDS and usual care groups. CONCLUSIONS: Although there were no significant differences in resource use or costs among CDS and usual care groups in the IMPACT-AF trial, this study provides insight into the methodology and practical challenges of collecting economic data alongside a trial. REGISTRATION: Clinicaltrials.gov (registration number: NCT01927367, date of registration: 2013-08-20).

Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF): A cluster randomized trial of a computerized clinical decision support tool.

BACKGROUND: Clinical decision support (CDS) tools designed to digest, filter, organize, and present health data are becoming essential in providing clinical and cost-effective care. Many are not rigorously evaluated for benefit before implementation. We assessed whether computerized CDS for primary care providers would improve atrial fibrillation (AF) management and outcomes as compared to usual care. METHODS: Overall, 203 primary care providers were recruited, randomized, and then cluster stratified by location (urban, rural) to usual care (n = 99) or CDS (n = 104). Providers recruited 1,145 adult patients with AF to participate. The intervention was access to an evidenced-based, point-of-care computerized CDS designed to support guideline-based AF management. The primary efficacy outcome was a composite of unplanned cardiovascular hospitalizations and AF-related emergency department visits; the primary safety outcome was major bleeding, both over 1 year. Patients were the units of intention-to-treat analysis. RESULTS: No significant effects on the primary efficacy (130 control, 118 CDS, hazard ratio: 0.98 [95% CI 0.71-1.37], P = .926) or safety (n = 7 usual care, n = 8 CDS, 1.3% total, P = .939) outcomes were observed at 12-months. CONCLUSIONS: IMPACT-AF rigorously assessed a CDS tool in a highly representative sample of primary care providers and their patients; however, no impact on outcomes was observed. Considering the proliferating use of CDS applications, this study highlights the need for efficacy assessments prior to adoption and clinical implementation.

Optimizing primary care management of atrial fibrillation: The rationale and methods of the Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) study.

The Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) is an investigator designed, prospective, randomized, un-blinded, cluster design clinical trial, conducted in the primary care setting of Nova Scotia, Canada. Its aim is to evaluate whether an electronic Clinical Decision Support System (CDSS) designed to assist both practitioners and patients with evidence-based management strategies for Atrial Fibrillation (AF) can improve process of care and outcomes in a cost-efficient manner as compared to usual AF care. At least 200 primary care providers are being recruited and randomized at the level of the practice to control (usual care) or intervention (eligible to access to CDSS) cohorts. Over 1,000 patients of participating providers with confirmed AF will be managed per their provider's respective assignment. The targeted primary clinical outcome is a reduction in the composite of unplanned cardiovascular (CV) or major bleeding hospitalizations and AF-related emergency department visits. Secondary clinical outcomes, process of care, patient and provider satisfaction as well as economic costs at the system and patient levels are being examined. The trial is anticipated to report in 2018.

Sputum colour and bacteria in chronic bronchitis exacerbations: a pooled analysis.

We examined the correlation between sputum colour and the presence of potentially pathogenic bacteria in acute exacerbations of chronic bronchitis (AECBs). Data were pooled from six multicentre studies comparing moxifloxacin with other antimicrobials in patients with an AECB. Sputum was collected before antimicrobial therapy, and bacteria were identified by culture and Gram staining. Association between sputum colour and bacteria was determined using logistic regression. Of 4,089 sputum samples, a colour was reported in 4,003; 1,898 (46.4%) were culture-positive. Green or yellow sputum samples were most likely to yield bacteria (58.9% and 45.5% of samples, respectively), compared with 18% of clear and 39% of rust-coloured samples positive for potentially pathogenic microorganisms. Factors predicting a positive culture were sputum colour (the strongest predictor), sputum purulence, increased dyspnoea, male sex and absence of fever. Green or yellow versus white sputum colour was associated with a sensitivity of 94.7% and a specificity of 15% for the presence of bacteria. Sputum colour, particularly green and yellow, was a stronger predictor of potentially pathogenic bacteria than sputum purulence and increased dyspnoea in AECB patients. However, it does not necessarily predict the need for antibiotic treatment in all patients with AECB.

Rhythm Control Vs Rate Control in a Contemporary Ambulatory Atrial Fibrillation Cohort: Post Hoc Analysis of the IMPACT-AF Trial.

Background: We examined the characteristics and outcomes in a contemporary ambulatory population of patients with atrial fibrillation (AF), comparing rate control with rhythm control. Methods: This is a post hoc analysis of a cluster-randomized trial (Integrated Management Program Advancing Community Treatment of Atrial Fibrillation [IMPACT-AF]) in ambulatory AF patients from 2016 to 2018, which compared use of a clinical decision support tool for general practitioners to usual care. This analysis compared patients managed with rate vs rhythm control, at entry into the study. Outcomes included AF-related emergency department (ED) visits, unplanned cardiovascular hospitalizations, and bleeding events at 12 months. Results: A total of 870 patients were included in this analysis, 99 (11.4%) in the rhythm-control group, and 40% women. In the rhythm-control group, the mean age was younger (70 ± 11.4 vs 72.7 ± 9.5 years, P = 0.03), a higher number were paroxysmal (80% vs 43%, P < 0.001), and CHADS2 scores were lower. The rate of AF-related ED visits was higher in the rhythm-control group (17.2 vs 7.3%, P = 0.003), and repeat visits (rate ratio 3.03, 95% confidence interval [1.99-4.52], P < 0.001). The number of repeat ED visits was independently associated with female sex and being in the rhythm-control group. Conclusions: Both rate- and rhythm-control patients have recurrent ED visits, with a higher rate in patients treated with rhythm control. These findings are observational, but taken in the context of current guidelines could help develop further therapies aimed at improving symptom burden in both rhythm- and rate-control patients to broadly improve healthcare utilization in the AF population.

Contexte: Nous avons examiné les caractéristiques et le devenir de patients ambulatoires contemporains atteints de fibrillation auriculaire (FA) dans le cadre d'une comparaison entre la maîtrise de la fréquence cardiaque et la maîtrise du rythme cardiaque. Méthodologie: Nous avons effectué une analyse a posteriori d'un essai à répartition aléatoire par grappes ( I ntegrated M anagement P rogram A dvancing C ommunity T reatment of A trial F ibrillation [IMPACT-AF]) mené de 2016 à 2018 chez des patients ambulatoires atteints de FA en vue de comparer un outil d'aide à la décision clinique destiné aux omnipraticiens avec les soins habituels. Notre analyse a permis d'établir une comparaison entre les patients pris en charge par une maîtrise de la fréquence cardiaque et ceux pris en charge par une maîtrise du rythme cardiaque lors de leur inscription à l'essai. Les paramètres d'évaluation comprenaient les consultations aux urgences liées à la FA, les hospitalisations imprévues ayant des causes cardiovasculaires et les épisodes hémorragiques à 12 mois. Résultats: Au total, 870 patients ont été inclus dans cette analyse; 99 (11,4 %) faisaient partie du groupe pris en charge par une maîtrise du rythme cardiaque, et 40 % étaient de femmes. Dans le groupe pris en charge par une maîtrise du rythme cardiaque, l'âge moyen était moindre (70 ± 11,4 ans vs 72,7 ± 9,5 ans, P = 0,03), un plus grand nombre de patients présentaient une FA paroxystique (80 % vs 43 %, P < 0,001) et les scores CHADS2 étaient moins élevés. Le taux de consultations aux urgences liées à la FA était plus élevé dans le groupe pris en charge par une maîtrise du rythme cardiaque (17,2 vs 7,3 %, P = 0,003) tout comme le taux de consultations répétées aux urgences (rapport des taux de 3,03, intervalle de confiance à 95 % de 1,99 à 4,52, P < 0,001). Le nombre de consultations répétées aux urgences était indépendamment associé au sexe féminin et à l'inclusion dans le groupe pris en charge par une maîtrise du rythme cardiaque. Conclusions: Des consultations répétées aux urgences ont été notées tant chez les patients pris en charge par une maîtrise de la fréquence cardiaque que chez ceux pris en charge par une maîtrise du rythme cardiaque quoique plus fréquemment chez ces derniers. Nos constats sont de type observationnel. Néanmoins, dans le contexte des lignes directrices actuelles, ils pourraient contribuer à la mise au point d'autres traitements visant à atténuer le fardeau des symptômes tant chez les patients pris en charge par une maîtrise du rythme cardiaque que chez ceux pris en charge par une maîtrise de la fréquence cardiaque et ainsi permettre globalement une meilleure utilisation des soins de santé chez les patients atteints de FA.

Colchicine and aspirin in community patients with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.

BACKGROUND: The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19. METHODS: The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0·6 mg twice daily for 3 days and then 0·6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing. FINDINGS: Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99% complete. Overall event rates were 5 (0·1%) of 3881 for major thrombosis, 123 (3·2%) of 3881 for hospitalisation, and 23 (0·6%) of 3881 for death; 66 (3·4%) of 1939 patients allocated to colchicine and 65 (3·3%) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1·02, 95% CI 0·72-1·43, p=0·93); and 59 (3·0%) of 1945 of patients allocated to aspirin and 73 (3·8%) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0·80, 95% CI 0·57-1·13, p=0·21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1·8%] of 1939 vs 27 [1·4%] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1·6%] vs 31 [1·6%]) and none that led to discontinuation of study interventions. INTERPRETATION: The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.

BACKGROUND: COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19. METHODS: The ACT inpatient, open-label, 2 × 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1·2 mg followed by 0·6 mg 2 h later and then 0·6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2·5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www. CLINICALTRIALS: gov, NCT04324463 and is ongoing. FINDINGS: Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98% complete. Overall, 368 (28·2%) of 1304 patients allocated to colchicine and 356 (27·2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1·04, 95% CI 0·90-1·21, p=0·58); and 281 (26·4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28·4%) of 1056 allocated to control had a primary outcome (HR 0·92, 95% CI 0·78-1·09, p=0·32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6·7%] of 1304 vs 90 [6·9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8·0%] vs 91 [8·6%]). Among patients assigned to colchicine, 8 (0·61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1·6%) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0·66%) of those allocated to control (p=0·042); the number of serious bleeding events was two (0·19%) versus six (0·57%), respectively (p=0·18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug. INTERPRETATION: Among patients hospitalised with COVID-19, neither colchicine nor the combination of rivaroxaban and aspirin prevent disease progression or death. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

The Anti-Coronavirus Therapies (ACT) Trials: Design, Baseline Characteristics, and Challenges.

Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging. Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death. Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.

Contexte: Il est urgent de mettre au point des traitements efficaces contre la COVID-19, mais il n'est pas facile de réaliser des essais à répartition aléatoire dans un contexte pandémique. Méthodologie: Les essais internationaux factoriels ACT (Anti-Coronavirus Therapy) avaient un objectif d'inscription de 3 500 patients externes et de 2 500 patients hospitalisés présentant une COVID-19 symptomatique. L'essai mené auprès de patients externes visait à évaluer la colchicine par rapport aux soins habituels, et l'aspirine par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était l'hospitalisation ou le décès dans le groupe traité par la colchicine, et la thrombose majeure, l'hospitalisation ou le décès dans le groupe traité par l'aspirine. L'essai mené auprès de patients hospitalisés visant à évaluer la colchicine par rapport aux soins habituels, et un traitement associant le rivaroxaban à 2,5 mg deux fois par jour et l'aspirine à 100 mg une fois par jour par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par la colchicine, et la survenue de manifestations thrombotiques majeures, le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par l'association rivaroxaban-aspirine. Résultats: À la fin de la période d'inscription, le 10 février 2022, 3 917 patients externes et 2 611 patients hospitalisés formaient la population des essais. Certains aspects se sont révélés problématiques, notamment le manque de données préliminaires sur les interventions à évaluer, les incertitudes liées aux taux d'événements prévus, les retards touchant les approbations réglementaires et éthiques et les interventions de recherche, de même que l'évolution de la pandémie de COVID-19. Conclusions: Les essais ACT détermineront l'efficacité du traitement anti-inflammatoire par la colchicine et du traitement antithrombotique par l'aspirine, administrée seule ou en association avec le rivaroxaban, contre la COVID-19 légère, modérée ou sévère. Les leçons tirées de ces essais orienteront la planification d'essais ultérieurs.

Lessons learned from Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF): a pragmatic clinical trial of computerized decision support in primary care.

BACKGROUND: Integrated Management Program Advancing Community Treatment of Atrial Fibrillation (IMPACT-AF) was a pragmatic, cluster randomized trial assessing the effectiveness of a clinical decision support (CDS) tool in primary care, Nova Scotia, Canada. We evaluated if CDS software versus Usual Care could help primary care providers (PCPs) deliver individualized guideline-based AF patient care. METHODS: Key study challenges including CDS development and implementation, recruitment, and data integration documented over the trial duration are presented as lessons learned. RESULTS: Adequate resources must be allocated for software development, updates and feasibility testing. Development took longer than projected. End-user feedback suggested network access and broadband speeds impeded uptake; they felt further that the CDS was not sufficiently user-friendly or efficient in supporting AF care (i.e., repetitive alerts). Integration across e-platforms is crucial. Intellectual property and other issues prohibited CDS integration within electronic medical records and provincial e-health platforms. Double login and data entry were impediments to participation or reasons for provider withdrawal. Data integration challenges prevented easy and timely data access, analysis, and reporting. Primary care study recruitment is resource intensive. Altogether, 203 PCPs and 1145 of their patients participated, representing 25% of eligible providers and 12% of AF patients in Nova Scotia, respectively. The most effective provider recruitment strategy was in-office, small group lunch-and-learns. PCPs with past research experience or who led patient consent were top recruiters. The study office played a pivotal role in achieving patient recruitment targets. CONCLUSIONS: A rapid growth in healthcare data is leading to widespread development of CDS. Our experience found practical issues to address for such applications to succeed. Feasibility testing to assess the utility of any healthcare CDS prior to implementation is recommended. Adequate resources are necessary to support successful recruitment for future pragmatic trials. CDS tools that integrate multiple co-morbid guidelines across eHealth platforms should be pursued. TRIAL REGISTRATION: ClinicalTrials.gov NCT01927367. Registered on August 22, 2013.

Patient-Reported Outcomes and Patient-Reported Experience of Patients With Atrial Fibrillation in the IMPACT-AF Clinical Trial.

Background The IMPACT-AF (Integrated Management Program Advancing Community Treatment of Atrial Fibrillation) trial is a prospective, randomized, cluster design trial comparing atrial fibrillation management with a computerized clinical decision support system with usual care (control) in the primary care setting of Nova Scotia, Canada. The objective of this analysis was to assess and compare patient-reported health-related quality of life and patient-reported experience with atrial fibrillation care between clinical decision support and control groups. Methods and Results Health-related quality of life was measured using the EuroQol 5-dimensional 5-level scale, whereas patient-reported experience was assessed using a self-administered satisfaction questionnaire, both assessed at baseline and 12 months. Health utilities were calculated using the Canadian EuroQol 5-dimensional 5-level value set. Descriptive statistics and generalized estimating equations were used to compare between groups. Among 1145 patients enrolled in the trial, 717 had complete EuroQol 5-dimensional 5-level data at baseline. The mean age of patients was 73.53 years, and 61.87% were men. Mean utilities at baseline were 0.809 (SD, 0.157) and 0.814 (SD, 0.157) for clinical decision support and control groups, respectively. At baseline, most patients in both groups reported being "very satisfied" with the care received for their atrial fibrillation. There were no statistically significant differences in utility scores or patient satisfaction between groups at 12 months. Conclusions Health-related quality of life of patients remained stable over 12 months, and there was no significant difference in patient satisfaction or utility scores between clinical decision support and control groups. Registration information clinicaltrials.gov. Identifier: NCT01927367.

Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis.

RATIONALE: Moxifloxacin has potent activity against Mycobacterium tuberculosis in vitro and in a mouse model of antituberculosis (TB) chemotherapy, but data regarding its activity in humans are limited. OBJECTIVES: Our objective was to compare the antimicrobial activity and safety of moxifloxacin versus isoniazid during the first 8 weeks of combination therapy for pulmonary TB. METHODS: Adults with sputum smear-positive pulmonary TB were randomly assigned to receive either moxifloxacin 400 mg plus isoniazid placebo, or isoniazid 300 mg plus moxifloxacin placebo, administered 5 days/week for 8 weeks, in addition to rifampin, pyrazinamide, and ethambutol. All doses were directly observed. Sputum was collected for culture every 2 weeks. The primary outcome was negative sputum culture at completion of 8 weeks of treatment. MEASUREMENTS AND MAIN RESULTS: Of 433 participants enrolled, 328 were eligible for the primary efficacy analysis. Of these, 35 (11%) were HIV positive, 248 (76%) had cavitation on baseline chest radiograph, and 213 (65%) were enrolled at African sites. Negative cultures at Week 8 were observed in 90/164 (54.9%) participants in the isoniazid arm, and 99/164 (60.4%) in the moxifloxacin arm (P = 0.37). In multivariate analysis, cavitation and enrollment at an African site were associated with lower likelihood of Week-8 culture negativity. The proportion of participants who discontinued assigned treatment was 31/214 (14.5%) for the moxifloxacin group versus 22/205 (10.7%) for the isoniazid group (RR, 1.35; 95% CI, 0.81, 2.25). CONCLUSIONS: Substitution of moxifloxacin for isoniazid resulted in a small but statistically nonsignificant increase in Week-8 culture negativity.

Moxifloxacin monotherapy is effective in hospitalized patients with community-acquired pneumonia: the MOTIV study--a randomized clinical trial.

BACKGROUND: The aim of this study was to show that sequential intravenous and oral moxifloxacin monotherapy (400 mg once per day) is as efficacious and safe as a combination regimen (intravenous ceftriaxone, 2 g once per day, plus sequential intravenous and oral levofloxacin, 500 mg twice per day) in patients hospitalized with community-acquired pneumonia. METHODS: We conducted a prospective, multicenter, randomized, double-blind noninferiority trial. Patients with a Pneumonia Severity Index (PSI) of III-V were stratified on the basis of PSI risk class before randomization. The primary efficacy end point was clinical response at test of cure (4-14 days after the completion of treatment). Secondary efficacy end points were clinical and bacteriological response at end of treatment (days 7-14) and at follow-up assessment (21-28 days after the end of treatment), overall mortality, and mortality attributable to pneumonia. RESULTS: Seven hundred thirty-three patients were enrolled in the study (368 in the moxifloxacin arm and 365 in the comparator arm); 49% had a PSI of IV, and 10% had a PSI of V. Of 569 patients (291 in the moxifloxacin arm and 278 in the comparator arm) valid for per-protocol analysis, the overall clinical cure rates at test of cure were 86.9% for moxifloxacin and 89.9% for the comparator regimen (95% confidence interval, -8.1% to 2.2%). Bacteriological success at test of cure was 83.3% for moxifloxacin and 85.1% for the comparator regimen (95% confidence interval, -15.4% to 11.8%). There were no significant differences between moxifloxacin and comparator treatments in the incidence of treatment-emergent adverse events or in mortality. CONCLUSIONS: Monotherapy with sequential intravenous/oral moxifloxacin was noninferior to treatment with ceftriaxone plus levofloxacin combination therapy in patients with community-acquired pneumonia who required hospitalization.

Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy.

We sought to determine the safety, maximum tolerated dose, optimal dose, and preliminary dose efficacy of intermittent subcutaneously (s.c.) administered BAY 50-4798 among patients with HIV infection receiving highly active antiretroviral therapy (HAART) compared with patients receiving HAART alone. A phase I/II randomized, double-blind, dose-escalation study was conducted of the safety, tolerability, pharmacokinetics, and efficacy of s.c. BAY 50-4798 administered to HIV-infected patients already receiving stable HAART. There were no unexpected safety findings in a population of HIV-infected patients receiving HAART plus SC BAY 50-4798 as adjunctive therapy. BAY 50-4798 exhibited nearly dose-proportional pharmacokinetics, and accumulation was minimal during multiple-dose treatment. Limited efficacy data indicated that treatment with BAY 50-4798 caused at least a transient increase in CD4(+) T cell counts in some recipients, particularly at the early time points. In general, this effect appeared to increase with increasing dose. Bay 50-4798 was generally well tolerated across the dose range tested, but a lack of potent, sustained immunologic activity suggests that further optimization of dose and schedule will be necessary.

Determination of moxifloxacin anaerobic susceptibility breakpoints according to the Clinical and Laboratory Standards Institute guidelines.

A summary of the key data presented to Clinical and Laboratory Standards Institute (CLSI, formerly National Committee for Clinical and Laboratory Standards) in determination of moxifloxacin anaerobic breakpoints is presented. The breakpoint analysis required review of a variety of data, including bacteriologic and clinical outcomes by MIC of anaerobic isolates from prospective clinical trials in patients with complicated intra-abdominal infections, human and animal pharmacokinetic/pharmacodynamic (PK/PD) information and in vitro models, MIC distributions of indicated organisms, and animal model efficacy data for strains with MIC values around prospective breakpoints. The compilation of the various components of this breakpoint analysis supports the US Food and Drug Administration (FDA) and CLSI moxifloxacin anaerobic breakpoints of < or =2 mg/L (susceptible), 4 mg/L (intermediate), and > or =8 mg/L (resistant), and provides information to European investigators for interpretation of MICs prior to establishment of the European Committee on Antimicrobial Susceptibility Testing breakpoints.

Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE): efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy.

BACKGROUND: Limited prospective data are available for elderly patients with community-acquired pneumonia (CAP). This study aimed to determine the efficacy and safety of moxifloxacin versus that of levofloxacin for the treatment of CAP in hospitalized elderly patients (age, > or = 65 years). METHODS: We conducted a prospective, double-blind, randomized, controlled trial. Eligible patients were stratified by CAP severity before randomization to receive treatment with either intravenous/oral moxifloxacin (400 mg daily) or intravenous/oral levofloxacin (500 mg daily) for 7-14 days. Clinical response at test-of-cure (the primary efficacy end point was between days 5 and 21 after completion of therapy), and clinical response during therapy (between days 3 and 5 after the start of therapy) and bacteriologic response were secondary end points. RESULTS: The safety population included 394 patients (195 in the moxifloxacin group and 199 in the levofloxacin group). The population eligible for clinical efficacy analysis (i.e., the clinically valid population) included 281 patients (141 in the moxifloxacin group and 140 in the levofloxacin group); 51.3% were male, and the mean age (+/-SD) was 77.4 +/- 7.7 years. Cure rates at test-of-cure for the clinically valid population were 92.9% in the moxifloxacin arm and 87.9% in the levofloxacin arm (95% confidence interval [CI], -1.9 to 11.9; P = .2). Clinical recovery by days 3-5 after the start of treatment was 97.9% in the moxifloxacin arm vs. 90.0% in the levofloxacin arm (95% CI, 1.7-14.1; P = .01). In the moxifloxacin group, cure rates were 92.6% for patients with mild or moderate CAP and 94.7% for patients with severe CAP, compared with cure rates of 88.6% and 84.6%, respectively, in the levofloxacin group (P = not significant). Cure rates in the moxifloxacin arm were 90.0% for patients aged 65-74 years and 94.5% for patients aged > or = 75 years, compared with 85.0% and 90.0%, respectively, in the levofloxacin arm (P = not significant). There were no statistically significant differences between the treatment groups with regard to drug-related adverse events. CONCLUSIONS: Intravenous/oral moxifloxacin therapy was efficacious and safe for hospitalized elderly patients with CAP, achieving > 90% cure in all severity and age subgroups, and was associated with faster clinical recovery than intravenous/oral levofloxacin therapy, with a comparable safety profile.

A randomized trial comparing the cardiac rhythm safety of moxifloxacin vs levofloxacin in elderly patients hospitalized with community-acquired pneumonia.

CONTEXT: Antimicrobial cardiac safety is of particular concern during the treatment of community-acquired pneumonia (CAP) in elderly patients, due to the presence of comorbid conditions and the use of multiple medications that may individually or synergistically affect cardiac repolarization. STUDY OBJECTIVE: To assess the cardiac rhythm safety of moxifloxacin vs levofloxacin in elderly patients hospitalized with CAP. DESIGN AND SETTING: Prospective, randomized, double-blind trial conducted at 47 hospitals in the United States. PATIENTS: Subjects > or = 65 years old with clinical signs/symptoms of CAP requiring initial parenteral therapy, including those with comorbidities. The safety population included 394 patients: 51.3% male; 85.3% white; mean age, 77.8 years. Two-thirds of the patients were > 75 years old, and 74.1% had a history of cardiac disease. INTERVENTIONS: Patients received IV/oral moxifloxacin (400 mg qd) or IV/oral levofloxacin (500 mg qd) for 7 to 14 days. Safety evaluations included 72 h of digital continuous 12-lead Holter monitoring, 12-lead ECGs at baseline and at maximum serum concentration on day 3, and adverse events. MAIN OUTCOME MEASURES: The primary safety end point was a composite of ventricular arrhythmia events based on Holter monitoring. RESULTS: Holter monitor data were available for 387 patients (192 receiving moxifloxacin and 195 receiving levofloxacin). Sixteen moxifloxacin-treated patients (8.3%) and 10 levofloxacin-treated patients (5.1%) had a primary composite cardiac event (p = 0.29); most events were nonsustained ventricular tachycardia (VT) [14 patients receiving moxifloxacin, 7.3%; and 10 patients receiving levofloxacin, 5.1%]. One moxifloxacin-treated patient had sustained monomorphic VT (> 30 s), and one levofloxacin-treated patient had torsade de pointes. Mean +/- SD QTc (Fridericia formula) change on day 3 was + 6.4 +/- 23.2 ms for moxifloxacin and - 2.5 +/- 22.9 ms for levofloxacin (p = 0.04). No deaths clearly related to study drugs occurred during the observation period. CONCLUSIONS: IV/oral moxifloxacin, although known to cause QTc interval prolongation, has a comparable cardiac rhythm safety profile to IV/oral levofloxacin in high-risk elderly patients with CAP.

Retrospective analysis of the safety profile of oral moxifloxacin in elderly patients enrolled in clinical trials.

BACKGROUND AND OBJECTIVE: As aging is associated with physiological changes, including renal and hepatic insufficiency, and a higher risk of drug interactions, special attention needs to be directed towards the safety of medications in the elderly. The objective of this analysis was to evaluate the safety of oral moxifloxacin in elderly patients who were enrolled in clinical trials and to compare these results to those of other commonly used antibacterials. METHODS: Safety data from 27 prospective, randomised, comparative phase II/III trials of oral moxifloxacin included in the Bayer clinical trial database were pooled and analysed by age group (<65 years of age, 65-74 years of age, > or = 75 years of age) and by treatment group (moxifloxacin vs comparator). The primary endpoints included rates of treatment-emergent adverse events (all adverse events regardless of causality), drug-related adverse events, drug-related serious adverse events, deaths and premature discontinuations because of a treatment-emergent adverse event. A treatment by age group interaction test was used to determine if the comparison between moxifloxacin and the comparator group in the incidence rates of any treatment-emergent or drug-related adverse events were affected by increasing age. RESULTS: Of the 12 231 patients who had valid safety data, 6270 had been treated with oral moxifloxacin and 5961 with a comparator antibacterial. The most frequently used comparators were cefuroxime and clarithromycin. Most patients (n = 9671) were <65 years of age (4939 moxifloxacin, 4732 comparator); 1636 patients were 65-74 years of age (842 moxifloxacin, 794 comparator); and 924 patients were > or = 75 years of age (489 moxifloxacin, 435 comparator). The treatment by age group interaction test revealed that the comparison of drug-related adverse event rates between the moxifloxacin and comparator group were not affected by increasing age (p = 0.43). Rates of premature termination between the moxifloxacin and comparator treatment groups also did not increase with age (p = 0.552). No arrhythmias related to corrected QT (QTc) interval prolongation were reported following oral moxifloxacin or comparator treatment in this large group of young and elderly patients. Overall, the number of deaths was similar between the treatment groups (17 moxifloxacin, 19 comparator). CONCLUSIONS: Drug-related adverse event rates associated with oral moxifloxacin or the comparator therapy used in these studies did not significantly increase with advancing age. This pooled analysis suggests that oral moxifloxacin can be safely used in elderly patients with characteristics consistent with those enrolled into the clinical trials.

Therapeutic enhancement of IL-2 through molecular design.

A recombinant human IL-2 analog (rIL-2, Proleukin) is currently being evaluated for clinical benefit in HIV infected patients. It is approved for therapy of patients with metastatic melanoma and renal cell carcinoma. Treatment of cancer patients with rIL-2 results in durable responses but is associated with life-threatening toxicity, which limits its use to patients in relatively good health. Antitumor efficacy associated with rIL-2 therapy are hypothesized to be mediated by distinct types of cells that express structurally different forms of the IL-2 receptor. This hypothesis suggests that it might be possible to engineer an IL-2 variant addressing the risks associated with the therapeutic use of IL-2. In this article, we review the clinical experience with IL-2 and its analogs, the evidence that different IL-2 receptors may dissociate efficacy and toxicity, and describe the generation of a novel IL-2 variant with the potential for a superior therapeutic index.