Triazole antifungal drug interactions-practical considerations for excellent prescribing.

Systemic antifungal therapy is critical for reducing the mortality from many invasive and chronic fungal infections. Triazole antifungals are the most frequently prescribed antifungals but require attention to dosing and drug interactions. Nearly 600 severe drug-drug interactions and over 1100 moderate interactions requiring dose modifications are described or anticipated with systemic antifungal agents (see https://www.aspergillus.org.uk/antifungal-drug-interactions/). In this article, we address the common and less common, but serious, drug interactions observed in clinical practice with triazole antifungals, including a group of drugs that cannot be prescribed with all or most triazole antifungals (ivabradine, ranolazine, eplerenone, fentanyl, apomorphine, quetiapine, bedaquiline, rifampicin, rifabutin, sirolimus, phenytoin and carbamazepine). We highlight interactions with drugs used in children and new agents introduced for the treatment of haematological malignancies or graft versus host disease (midostaurin, ibrutinib, ruxolitinib and venetoclax). We also summarize the multiple interactions between oral and inhaled corticosteroids and triazole antifungals, and the strategies needed to optimize the therapeutic benefits of triazole antifungal therapy while minimizing potential harm to patients.

Determinants of Response to Roflumilast in Severe Chronic Obstructive Pulmonary Disease. Pooled Analysis of Two Randomized Trials.

RATIONALE: Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations. Further characterization of patients most likely to benefit is warranted. OBJECTIVES: Define characteristics that most robustly identify patients who derive greatest exacerbation risk reduction with roflumilast. METHODS: Predefined, pooled analyses of REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment; NCT01329029) and RE2SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy; NCT01443845) multicenter, randomized, double-blind, placebo-controlled studies. The primary endpoint was rate of moderate or severe exacerbations per patient per year. MEASUREMENTS AND MAIN RESULTS: In the overall intention-to-treat population (n = 4,287), roflumilast reduced moderate or severe exacerbations by 12.3% (rate ratio, 0.88, 95% confidence interval, 0.80-0.97; P = 0.0086) and severe exacerbations by 16.1% (0.84; 0.71-0.99; P = 0.0409) versus placebo. The reduction in moderate or severe exacerbations with roflumilast was most pronounced in patients who had been hospitalized for an exacerbation in the prior year (0.74; 0.63-0.88; P = 0.0005); had more than two exacerbations in the prior year (0.79; 0.65-0.96; P = 0.0160); or had baseline eosinophils ≥150 cells/µl (0.81; 0.71-0.93; P = 0.0020), ≥150 to <300 cells/µl (0.84; 0.71-0.98; P = 0.0282), or ≥300 cells/µl (0.77; 0.61-0.97; P = 0.0264). Similar subgroup results were noted for severe exacerbations. In patients with prior hospitalization and higher baseline blood eosinophil concentrations, roflumilast reduced moderate or severe exacerbations by 34.5% at ≥150 cells/µl (0.65; 0.52-0.82; P = 0.0003) and 42.7% at ≥300 cells/µl (0.57; 0.37-0.88; P = 0.0111) versus placebo. CONCLUSIONS: This prespecified, pooled analysis confirms the benefit of roflumilast in decreasing exacerbations in patients with prior hospitalization for exacerbation, greater exacerbation frequency, and higher (≥150 cells/µl, ≥150 to <300 cells/µl, or ≥300 cells/µl) baseline blood eosinophil count.

Vaccine strategies for prevention of community-acquired pneumonia in Canada: Who would benefit most from pneumococcal immunization?

OBJECTIVE: To describe the burden of pneumococcal disease and associated risk factors in the Canadian adult population, delineate available pneumococcal vaccines and associated efficacy and effectiveness data, and review current pneumococcal vaccine recommendations and community-acquired pneumonia (CAP) prevention strategies in Canada. QUALITY OF EVIDENCE: Pneumococcal vaccination guidelines from the Canadian National Advisory Committee on Immunization in 2013 and 2016 constitute level III evidence for CAP prevention in the Canadian adult population. MAIN MESSAGE: It is recommended that immunosuppressed adults of all ages receive the 13-valent pneumococcal conjugate vaccine (PCV13) (grades A and B recommendations). In 2016, the National Advisory Committee on Immunization also recommended that all adults aged 65 years and older receive PCV13 (grade A recommendation) on an individual basis, followed by the 23-valent pneumococcal polysaccharide vaccine (grade B recommendation). This update is based on a large clinical study that demonstrated PCV13 efficacy against vaccine-type CAP in this population. CONCLUSION: Physicians should focus on improving pneumococcal vaccination rates among adults, which remain low. Vaccination with PCV13 should also be considered for adults with chronic conditions, whose baseline risk is often higher than that for healthy individuals aged 65 years and older.

Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting ß2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial.

RATIONALE: Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease. OBJECTIVES: To determine whether roflumilast reduces moderate and/or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting ß2-agonist with or without a long-acting muscarinic antagonist (LAMA). METHODS: In this 52-week, phase 4, double-blind, placebo-controlled RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy) trial (NCT01443845), participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease, chronic bronchitis, two or more exacerbations and/or hospitalizations in the previous year, and receiving inhaled corticosteroid/long-acting ß2-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 µg (n = 1,178), or placebo (n = 1,176). Stratification was based on LAMA use. MEASUREMENTS AND MAIN RESULTS: Although rate of moderate or severe exacerbations per patient per year (primary endpoint) was reduced by 8.5% with roflumilast versus placebo, the between-group difference was not statistically significant (rate ratio, 0.92; 95% confidence interval, 0.81-1.04; P = 0.163). However, roflumilast improved lung function, and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and/or one or more hospitalizations in the prior year. Adverse event-related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants. CONCLUSIONS: Roflumilast failed to statistically significantly reduce moderate and/or severe exacerbations in the overall population. Roflumilast improved lung function and reduced exacerbations in participants with frequent exacerbations and/or hospitalization history. The safety profile of roflumilast was consistent with that of previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT01443845).

Introducing the COPD Foundation Guide for Diagnosis and Management of COPD, recommendations of the COPD Foundation.

The increasing number of treatment options for managing patients with chronic obstructive pulmonary disease (COPD) promises to improve the outcomes for COPD patients. However, determining which treatments are appropriate for individual patients has become increasingly complex. The COPD Foundation Guide for Diagnosis and Management of COPD was developed to be a practical, easy to use tool for clinicians. The Guide includes specific recommendations for diagnostic studies and treatments based on specific diagnostic criteria. This manuscript describes the rationale for the development of the Guide, the process used, the rationale for the specific recommendations and the plans for further development. The current recommendations of the COPD Foundation have been summarized in the form of Pocket Cards, which may be obtained from the Foundation at no charge (1-866-316-COPD (2673), www.copdfoundation.org).

Evaluation outcomes resulting from an internet-based continuing professional development (CPD) asthma program: its impact on participants' knowledge and satisfaction.

INTRODUCTION: Previous studies have focused on the evaluation of Internet-based continuing professional development (CPD), but few have focused on the clinical area of asthma. Our purpose was to examine the evaluation outcomes related to knowledge and satisfaction that resulted from the provision of an Internet-based CPD program focusing on this clinical area. METHODS: Evaluation methodologies included a pre-/post-knowledge assessment (multiple choice) and a satisfaction survey. Completion of all assessments was voluntary, with the exception of the post-knowledge assessment for which completion was required for credit claim. RESULTS: There were a total of N = 457 unique registrants in the course over 1 year. A total of N = 125 course participants completed both pre- and post-knowledge assessments. An overall mean pre-knowledge score of 11.54 and a post-knowledge score of 16.04 were reported. Paired samples t-test analyses indicated a significant pre- to post-knowledge gain overall and for the majority of professions; 95.8% of the N = 46 satisfaction survey respondents reported that the program addressed their learning needs; 89.1% reported that it was relevant to practice. DISCUSSION: Recent studies focusing specifically on asthma were non-Canadian pilot studies with small sample sizes. The study findings highlight a similar initiative in Canada, which provided health professionals who care for patients with asthma access to relevant CPD with a Canadian perspective. The findings show that course participants were extremely satisfied and that they increased their knowledge in this clinical area. Further development of such Internet-based programs may encourage health professionals to improve their knowledge in a variety of therapeutic areas.

Global Quality Statements on Reliever Use in Asthma in Adults and Children Older than 5 Years of Age.

INTRODUCTION: Widespread misuse of short-acting beta-agonists (SABAs) may contribute to asthma-related morbidity and mortality. Recognizing this, the Global Initiative for Asthma neither recommends SABA monotherapy nor regards this formulation as a preferred reliever. Many health systems and healthcare professionals (HCPs) experience practical issues in implementing guidelines. Clear quality standards can drive improvements in asthma care and encourage implementation of global and national medical guidelines. METHODS: A steering group of global asthma experts came together between May and September 2019 to develop quality statements codifying the minimum elements of good quality asthma care. These statements were either evidence based (when robust evidence was available) or reflected a consensus based on clinical expertise and experience of the group. RESULTS: The quality statements (and associated essential criteria) developed emphasize key elements concerning (1) objective diagnosis specific to individual symptoms, (2) treatment appropriate to the long-term management of asthma as an inflammatory disease, consistent with evidence-based recommendations, (3) controlled dispensing of SABA canisters and monitoring to prevent overuse, (4) regular review of patients after treatment initiation or change, and (5) follow-up of patients in primary care after treatment for an exacerbation in a hospital or an emergency department. CONCLUSIONS: The steering group proposes quality statements that national and local clinical groups can implement as quantitative quality standards that are appropriate to their local circumstances, including during the coronavirus disease 2019 (Covid-19) pandemic. By translating these statements into locally relevant quality standards, primary care physicians and HCPs can encourage optimal management and reduce preventable healthcare interactions. The evidence-based evolution of care encapsulated in these statements will further engender high-quality, patient-centered holistic management that addresses asthma as an inflammatory disease. In particular, the statements empower self-management by patients and encourage health-promoting behaviors, which are essential to reduce exacerbations, the primary goal of asthma management.

Blood Eosinophils and Pulmonary Rehabilitation in COPD.

Background: Blood eosinophils predict the response to therapy, risk of exacerbation, and readmission in COPD. This study investigates whether blood eosinophils predict pulmonary rehabilitation (PR) outcomes in COPD. Methods: We categorized patients into eosinophilic (blood eosinophils ≥300 cells/ml) or noneosinophilic (<300 cells/ml). In a retrospective design, we compared changes within and between the two groups on BODE index, 6-minute walk test (6MWT), FEV1, and mMRC dyspnea scale. Results: Of 206 patients enrolled, 176 were included for analysis; 90 were eosinophilic. BODE index improved in both groups: (MD -1.25; 95% CI (-0.45, -4.25), P ≤ 0.001) in the eosinophilic and (MD -1.33; 95% CI (-1.72, -0.94), P ≤ 0.001) in the noneosinophilic, but a higher BODE index remained in the eosinophilic (4.98); adjusted mean change (ß): 0.7 (95% CI (0.15, 1.26), P=0.01). 6MWT improved by 29.3 m in the eosinophilic (95% CI (14.2, 44.4), P ≤ 0.001) vs. 115.1 m in the noneosinophilic (95% CI (-30.4, 260.6), P=0.12). FEV1 did not change in the eosinophilic (MD -0.6; 95% CI (-2.64, 1.48), P=0.58), but improved by 2.5% in the noneosinophilic (MD 2.5; 95% CI (0.77, 4.17), P=0.005). There were no significant between-group differences in 6MWT and FEV1; adjusted mean changes (ß) were -9.69 m (95% CI (-39.51, 20.14), P=0.52) and -2.31% (95% CI (-5.69, 1.08), P=0.18), respectively. There were no significant within- or between-group changes in the mMRC scale. Conclusion: Although PR improves the BODE index in both eosinophilic and noneosinophilic COPD, a higher eosinophil count (≥300 cells/ml) is associated with a higher (worse) BODE index. Blood eosinophils may predict PR outcomes.

Effect of smoking on lung function, respiratory symptoms and respiratory diseases amongst HIV-positive subjects: a cross-sectional study.

BACKGROUND: Smoking prevalence in human immunodeficiency virus (HIV) positive subjects is about three times of that in the general population. However, whether the extremely high smoking prevalence in HIV-positive subjects affects their lung function is unclear, particularly whether smoking decreases lung function more in HIV-positive subjects, compared to the general population. We conducted this study to determine the association between smoking and lung function, respiratory symptoms and diseases amongst HIV-positive subjects. RESULTS: Of 120 enrolled HIV-positive subjects, 119 had an acceptable spirogram. Ninety-four (79%) subjects were men, and 96 (81%) were white. Mean (standard deviation [SD]) age was 43.4 (8.4) years. Mean (SD) of forced expiratory volume in one second (FEV1) percent of age, gender, race and height predicted value (%FEV1) was 93.1% (15.7%). Seventy-five (63%) subjects had smoked 24.0 (18.0) pack-years. For every ten pack-years of smoking increment, %FEV1 decreased by 2.1% (95% confidence interval [CI]: -3.6%, -0.6%), after controlling for gender, race and restrictive lung function (R2 = 0.210). The loss of %FEV1 in our subjects was comparable to the general population. Compared to non-smokers, current smokers had higher odds of cough, sputum or breathlessness, after adjusting for highly active anti-retroviral therapy (HAART) use, odds ratio OR = 4.9 (95% CI: 2.0, 11.8). However respiratory symptom presence was similar between non-smokers and former smokers, OR = 1.0 (95% CI: 0.3, 2.8). All four cases of COPD (chronic obstructive pulmonary disease) had smoked. Four of ten cases of restrictive lung disease had smoked (p = 0.170), and three of five asthmatic subjects had smoked (p = 1.000). CONCLUSIONS: Cumulative cigarette consumption was associated with worse lung function; however the loss of %FEV1 did not accelerate in HIV-positive population compared to the general population. Current smokers had higher odds of respiratory symptoms than non-smokers, while former smokers had the same odds of respiratory symptoms as non-smokers. Cigarette consumption was likely associated with more COPD cases in HIV-positive population; however more participants and longer follow up would be needed to estimate the effect of smoking on COPD development. Effective smoking cessation strategies are required for HIV-positive subjects.

Understanding Patient Perspectives on Medication Adherence in Asthma: A Targeted Review of Qualitative Studies.

Adherence to asthma medications is generally poor and undermines clinical outcomes. Poor adherence is characterized by underuse of inhaled corticosteroids (ICS), often accompanied by over-reliance on short-acting ß2-agonists for symptom relief. To identify drivers of poor medication adherence, a targeted literature search was performed in MEDLINE and EMBASE for articles presenting qualitative data evaluating medication adherence in asthma patients (≥12 years old), published from January 1, 2012 to February 26, 2018. A thematic analysis of 21 relevant articles revealed several key themes driving poor medication adherence, including asthma-specific drivers and more general drivers common to chronic diseases. Due to the episodic nature of asthma, many patients felt that their daily life was not substantially impacted; consequently, many harbored doubts about the accuracy of their diagnosis or were in denial about the impact of the disease and, in turn, the need for long-term treatment. This was further compounded by poor patient-physician communication, which contributed to suboptimal knowledge about asthma medications, including lack of understanding of the distinction between maintenance and reliever inhalers, suboptimal inhaler technique, and concerns about ICS side effects. Other drivers of poor medication adherence included the high cost of asthma medication, general forgetfulness, and embarrassment over inhaler use in public. Overall, patients' perceived lack of need for asthma medications and medication concerns, in part due to suboptimal knowledge and poor patient-physician communication, emerged as key drivers of poor medication adherence. Optimal asthma care and management should therefore target these barriers through effective patient- and physician-centered strategies.

Usage Patterns of Short-Acting ß2-Agonists and Inhaled Corticosteroids in Asthma: A Targeted Literature Review.

Despite the availability of effective asthma treatments, some patients are poorly controlled because of overreliance on short-acting ß2-agonists (SABAs) and underuse of inhaled corticosteroids (ICSs). To identify patient characteristics and outcomes associated with SABA overreliance and ICS underuse, we conducted a targeted literature review of the quantitative evidence on asthma medication use. Articles evaluating SABA and/or ICS use in patients with asthma (aged ≥12 years), published between January 2012 and March 2018, were identified using MEDLINE and EMBASE. We observed that studies classified SABA usage as "overuse," "high use," "excess use," "extreme overuse," "suboptimal use," and "inappropriate use." Multiple thresholds were used to define overuse of SABA (≥3 to ≥12 canisters/y). SABA overreliance was prevalent, with approximately 20% of adults using 3 or more canisters per year (≥12 inhalations/wk). Similarly, inappropriate ICS use, classified as "suboptimal," "high use," "underuse," and "unlicensed use," was defined by varying thresholds. Specific patient populations, such as older adults, smokers, and patients with low income, were more susceptible to SABA overreliance and ICS underuse. Overreliance on SABAs was associated with increased risk of severe exacerbations, asthma-related hospitalizations, emergency department visits, and asthma-related costs. These findings emphasize the prevalence and related burden of SABA overreliance at the potential expense of appropriate ICS use.

Tobacco control and nicotine addiction in Canada: current trends, management and challenges.

Despite a significant decrease in tobacco use over the past four decades, cigarette smoking remains the leading preventable cause of death and disease in Canada. Nicotine addiction, unequal access to available support programs and gaps in continuity of health care are recognized as the main barriers to smoking cessation. To overcome these obstacles and to reach the Federal Tobacco Control Strategy goal of reducing smoking prevalence in Canada from 19% to 12% by 2011, several Canadian health care organizations developed extensive sets of recommendations. Improved access to affordable pharmacotherapies and behavioural counselling, better training of health care professionals and the addition of systemic cessation measures appear to be the key components in all of the proposed recommendations. The present article provides an overview of the current approaches to smoking cessation in Canada, describes the remaining challenges, and outlines recent recommendations that are geared toward not only tobacco control but also overall improvement in long-term health outcomes.

Cost-Effectiveness of the Aerobika® Oscillating Positive Expiratory Pressure Device in the Management of Chronic Obstructive Pulmonary Disease Exacerbations in Canada.

Background: The Aerobika® oscillating positive expiratory pressure (OPEP) device is a hand-held, drug-free medical device that has been shown to improve lung function and improve health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). We estimated the cost-effectiveness of this device among postexacerbation COPD patients in the Canadian healthcare system. Methods: We performed a cost-utility analysis using a Markov model to compare both costs and outcome of patients with COPD who had recently experienced an exacerbation between 2 treatment arms: patients who used the Aerobika® device and patients who did not use the Aerobika® device. This cost-utility analysis included costs based on the Alberta healthcare system perspective as these represent Canadian experience. A one-year horizon with 12 monthly cycles was used. Results: For a patient after 1 year, the use of the Aerobika® device would save $694 in healthcare costs and produce 0.04 more in quality-adjusted life years (QALYs) in comparison with no positive expiratory pressure (PEP)/OPEP therapy. In other words, the economic outcome of the device was dominant (i.e., more effective and less costly). The probability for this device to be the dominant strategy was 72%. With a willingness to pay (WTP) threshold of $50,000 per QALY gained, the probability for the Aerobika® device to be cost-effective was 77%. Conclusions: Given one of the major treatment goals in the GOLD guidelines is to minimize the negative impact of exacerbations and prevent re-exacerbations, the Aerobika® OPEP device should be viewed as a potential component of a treatment strategy to improve symptom control and reduce the risk of re-exacerbations in patients with COPD.

Corrigendum to "Cost-Effectiveness of the Aerobika® Oscillating Positive Expiratory Pressure Device in the Management of Chronic Obstructive Pulmonary Disease Exacerbations in Canada".

[This corrects the article DOI: 10.1155/2019/9176504.].

Real-life effectiveness of indacaterol-glycopyrronium after switching from tiotropium or salmeterol/fluticasone therapy in patients with symptomatic COPD: the POWER study.

PURPOSE: In contrast to randomized controlled trials (RCTs), changes in maintenance pharmacotherapy in clinical practice occur without a washout period. The Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium With indacatERol combination in the management of COPD in Canada (POWER) study evaluated the real-life effectiveness of indacaterol/glycopyrronium (IND/GLY) following a direct switch from a long-acting muscarinic antagonist (LAMA, tiotropium) or long-acting ß2-agonist (LABA)/inhaled corticosteroid (ICS) maintenance treatment (salmeterol/fluticasone [SFC]). METHODS: POWER was a single-cohort, prospective, multicenter, interventional study in which patients with moderate-to-severe COPD, who remained symptomatic on their current treatment of once-daily (od) tiotropium 18 µg or twice-daily (bid) SFC (any dose), were switched to treatment with open-label IND/GLY 110/50 µg od for 16 weeks. Effectiveness end points were change from baseline in trough FEV1, transition dyspnea index (TDI) total scores, and COPD assessment test (CAT) scores at 16 weeks. RESULTS: Trough FEV1 improved by 175 mL at Week 16 in patients who switched to IND/GLY. The change was 176 mL (95% CI: 135-217) when switched from tiotropium and 172 mL (95% CI: 85-258) when switched from SFC fixed-dose combination (FDC). At Week 16, significant improvements were observed in the mean TDI total scores (Δ=2.5) and CAT scores (Δ=-6.5) after the switch to IND/GLY treatment (both P<0.0001). Additionally, IND/GLY was well tolerated in patients with moderate-to-severe COPD, and no safety signal was observed. CONCLUSION: In clinical practice settings, a direct switch from previous treatment with either tiotropium or SFC to IND/GLY was safe and provided superior clinically significant improvements in lung function and patient-related outcomes in patients with moderate-to-severe COPD. CLINICAL TRIAL REGISTRATION: NCT02202616.

Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.

BACKGROUND: Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied. OBJECTIVE: To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006. SETTING: 27 academic and community medical centers in Canada. PATIENTS: 449 patients with moderate or severe COPD. INTERVENTION: 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol. MEASUREMENTS: The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics. RESULTS: The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo. LIMITATIONS: More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists. CONCLUSIONS: Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.

Canadian economic evaluation of budesonide-formoterol as maintenance and reliever treatment in patients with moderate to severe asthma.

OBJECTIVES: To compare the cost-effectiveness of budesonide-formoterol in a single inhaler used as both maintenance and reliever medication versus clinician-directed titration of salmeterol-fluticasone as maintenance medication, plus salbutamol taken as needed, in controlling asthma in adults and adolescents. METHODS: A Canadian economic evaluation was conducted based on the results of a large (n=2143), open-label, randomized, controlled effectiveness trial in which health resource use was prospectively collected. The primary outcome measurement was the time to the first severe exacerbation. Costs included direct medical costs (physician and emergency room visits, hospitalizations, asthma drug costs, etc) and productivity (absenteeism). The time horizon was one year, which corresponded to the duration of the clinical trial. Prices were obtained from 2005 Canadian sources. Both health care and societal perspectives were considered, and deterministic univariate sensitivity analyses were conducted. RESULTS: In the clinical trial, budesonide-formoterol as maintenance and reliever treatment was superior to salmeterol-fluticasone with respect to the time to the first severe exacerbation, overall rate of exacerbations and use of as-needed reliever medication. The annualized rate of severe exacerbations was 0.24 events/patient in the budesonide-formoterol arm and 0.31 events/patient in the salmeterol-fluticasone arm (P=0.0025). From a health care perspective, the mean cost per patient-year was $1,315 in the budesonide-formoterol arm versus $1,541 in the salmeterol-fluticasone arm. From a societal perspective, the mean cost per patient-year was $1,538 in the budesonide-formoterol arm and $1,854 in the salmeterol-fluticasone arm. Budesonide-formoterol was dominant (more effective and less expensive) in the base case analysis from both perspectives. The results were robust under sensitivity testing. CONCLUSIONS: The strategy that allows budesonide-formoterol to be used in a single inhaler as both maintenance and reliever medication proved to be more effective and less expensive than a strategy of clinician-directed titration of salmeterol-fluticasone with salbutamol as reliever therapy.

Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids.

Long-acting beta-agonists are a pillar of therapy for many patients with asthma because they are the preferred add-on therapy to inhaled corticosteroids. However, a recent meta-analysis documented a substantial increase in severe exacerbations requiring hospital admission and life-threatening asthma exacerbations in patients treated with long-acting beta-agonists. A careful evaluation of this meta-analysis raises several concerns about its applicability to current practice. Pivotal trials evaluating the benefit of adding long-acting beta-agonists to inhaled corticosteroids were not included. The authors of the current paper call for physicians to continue their usual practice of using long-acting beta-agonists as adjunctive therapy, as well as for an independent meta-analysis of individual patients using inhaled corticosteroids and long-acting beta-agonists concomitantly.

GOLD Stage and Treatment in COPD: A 500 Patient Point Prevalence Study.

Background and Objective: The Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines recommend using a combination of spirometry, symptoms and exacerbation history to classify patients into 4 categories (A, B, C, D) to guide treatment decisions along with a stepwise increase in therapy. Our objectives were to identify the GOLD stage of patients in respiratory outpatient clinics and assess how treatment compares to guideline recommendations. Methods: This was a point prevalence study using a convenience sample of 500 patients with chronic obstructive pulmonary disease (COPD) from a single tertiary care outpatient respiratory clinic. Results: Patients' GOLD classification was determined based on symptoms (modified Medical Research Council [mMRC] dyspnea scale, COPD Assessment Test [CAT]), spirometry and self-reported exacerbation history. A total of 8.2% of patients were in the GOLD group A, 28.3% in group B, 4.2% in group C and 59.2% in group D. Conclusions: In this 500 patient point prevalence study we report a low proportion of patients in GOLD group C and a high level of inhaled corticosteroids (ICS)/ long-acting beta2-agonist (LABA) and triple therapy use throughout all GOLD categories. Clinical Implications: The GOLD guidelines have attempted to provide direction to practitioners by grouping patients into 4 groups based on symptoms and exacerbations however, the low prevalence of GOLD group C may indicate that not all of these groupings are clinically relevant. Future research is needed to better identify clinically relevant phenotypes that predict benefit from ICS and methods to promote guideline concordant management in COPD.