Inhaled Combined Budesonide–Formoterol as Needed in Mild Asthma

BACKGROUND

In patients with mild asthma, as-needed use of an inhaled glucocorticoid plus a fast-acting β2-agonist may be an alternative to conventional treatment strategies.

METHODS

We conducted a 52-week, double-blind trial involving patients 12 years of age or older with mild asthma. Patients were randomly assigned to one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide–formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed (budesonide–formoterol group), or twice-daily budesonide (200 μg) plus terbutaline used as needed (budesonide maintenance group). The primary objective was to investigate the superiority of as-needed budesonide–formoterol to as-needed terbutaline with regard to electronically recorded weeks with well-controlled asthma.

RESULTS

A total of 3849 patients underwent randomization, and 3836 (1277 in the terbutaline group, 1277 in the budesonide–formoterol group, and 1282 in the budesonide maintenance group) were included in the full analysis and safety data sets. With respect to the mean percentage of weeks with well-controlled asthma per patient, budesonide–formoterol was superior to terbutaline (34.4% vs. 31.1% of weeks; odds ratio, 1.14; 95% confidence interval [CI], 1.00 to 1.30; P=0.046) but inferior to budesonide maintenance therapy (34.4% and 44.4%, respectively; odds ratio, 0.64; 95% CI, 0.57 to 0.73). The annual rate of severe exacerbations was 0.20 with terbutaline, 0.07 with budesonide–formoterol, and 0.09 with budesonide maintenance therapy; the rate ratio was 0.36 (95% CI, 0.27 to 0.49) for budesonide–formoterol versus terbutaline and 0.83 (95% CI, 0.59 to 1.16) for budesonide–formoterol versus budesonide maintenance therapy. The rate of adherence in the budesonide maintenance group was 78.9%. The median metered daily dose of inhaled glucocorticoid in the budesonide–formoterol group (57 μg) was 17% of the dose in the budesonide maintenance group (340 μg).

CONCLUSIONS

In patients with mild asthma, as-needed budesonide–formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide–formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy. (Funded by AstraZeneca; SYGMA 1 ClinicalTrials.gov number, NCT02149199.)

Reference: N Engl J Med 2018; 378:1865-1876

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Cardiovascular disease risk prediction equations in 400 000 primary care patients in New Zealand: a derivation and validation study

Background

Most cardiovascular disease risk prediction equations in use today were derived from cohorts established last century and with participants at higher risk but less socioeconomically and ethnically diverse than patients they are now applied to. We recruited a nationally representative cohort in New Zealand to develop equations relevant to patients in contemporary primary care and compared the performance of these new equations to equations that are recommended in the USA.

Methods

The PREDICT study automatically recruits participants in routine primary care when general practitioners in New Zealand use PREDICT software to assess their patients’ risk profiles for cardiovascular disease, which are prospectively linked to national ICD-coded hospitalisation and mortality databases. The study population included male and female patients in primary care who had no prior cardiovascular disease, renal disease, or congestive heart failure. New equations predicting total cardiovascular disease risk were developed using Cox regression models, which included clinical predictors plus an area-based deprivation index and self-identified ethnicity. Calibration and discrimination performance of the equations were assessed and compared with 2013 American College of Cardiology/American Heart Association Pooled Cohort Equations (PCEs). The additional predictors included in new PREDICT equations were also appended to the PCEs to determine whether they were independent predictors in the equations from the USA.

Findings

Outcome events were derived for 401 752 people aged 30–74 years at the time of their first PREDICT risk assessment between Aug 27, 2002, and Oct 12, 2015, representing about 90% of the eligible population. The mean follow-up was 4·2 years, and a third of participants were followed for 5 years or more. 15 386 (4%) people had cardiovascular disease events (1507 [10%] were fatal, and 8549 [56%] met the PCEs definition of hard atherosclerotic cardiovascular disease) during 1 685 521 person-years follow-up. The median 5-year risk of total cardiovascular disease events predicted by the new equations was 2·3% in women and 3·2% in men. Multivariable adjusted risk increased by about 10% per quintile of socioeconomic deprivation. Māori, Pacific, and Indian patients were at 13–48% higher risk of cardiovascular disease than Europeans, and Chinese or other Asians were at 25–33% lower risk of cardiovascular disease than Europeans. The PCEs overestimated of hard atherosclerotic cardiovascular disease by about 40% in men and by 60% in women, and the additional predictors in the new equations were also independent predictors in the PCEs. The new equations were significantly better than PCEs on all performance metrics.

Interpretation

We constructed a large prospective cohort study representing typical patients in primary care in New Zealand who were recommended for cardiovascular disease risk assessment. Most patients are now at low risk of cardiovascular disease, which explains why the PCEs based mainly on old cohorts substantially overestimate risk. Although the PCEs and many other equations will need to be recalibrated to mitigate overtreatment of the healthy majority, they also need new predictors that include measures of socioeconomic deprivation and multiple ethnicities to identify vulnerable high-risk subpopulations that might otherwise be undertreated.

Funding

Health Research Council of New Zealand, Heart Foundation of New Zealand, and Healthier Lives National Science Challenge.

Reference: The Lancet, Volume 391, No. 10133, p1897–1907, 12 May 2018

Emollient bath additives for the treatment of childhood eczema (BATHE)

Objectives To determine the clinical effectiveness and cost effectiveness of including emollient bath additives in the management of eczema in children.

Design Pragmatic randomised open label superiority trial with two parallel groups.

Setting 96 general practices in Wales and western and southern England.

Participants 483 children aged 1 to 11 years, fulfilling UK diagnostic criteria for atopic dermatitis. Children with very mild eczema and children who bathed less than once weekly were excluded.

Interventions Participants in the intervention group were prescribed emollient bath additives by their usual clinical team to be used regularly for 12 months. The control group were asked to use no bath additives for 12 months. Both groups continued with standard eczema management, including leave-on emollients, and caregivers were given standardised advice on how to wash participants.

Main outcome measures The primary outcome was eczema control measured by the patient oriented eczema measure (POEM, scores 0-7 mild, 8-16 moderate, 17-28 severe) weekly for 16 weeks. Secondary outcomes were eczema severity over one year (monthly POEM score from baseline to 52 weeks), number of eczema exacerbations resulting in primary healthcare consultation, disease specific quality of life (dermatitis family impact), generic quality of life (child health utility-9D), utilisation of resources, and type and quantity of topical corticosteroid or topical calcineurin inhibitors prescribed.

Results 483 children were randomised and one child was withdrawn, leaving 482 children in the trial: 51% were girls (244/482), 84% were of white ethnicity (447/470), and the mean age was 5 years. 96% (461/482) of participants completed at least one post-baseline POEM, so were included in the analysis, and 77% (370/482) completed questionnaires for more than 80% of the time points for the primary outcome (12/16 weekly questionnaires to 16 weeks). The mean baseline POEM score was 9.5 (SD 5.7) in the bath additives group and 10.1 (SD 5.8) in the no bath additives group. The mean POEM score over the 16 week period was 7.5 (SD. 6.0) in the bath additives group and 8.4 (SD 6.0) in the no bath additives group. No statistically significant difference was found in weekly POEM scores between groups over 16 weeks. After controlling for baseline severity and confounders (ethnicity, topical corticosteroid use, soap substitute use) and allowing for clustering of participants within centres and responses within participants over time, POEM scores in the no bath additives group were 0.41 points higher than in the bath additives group (95% confidence interval −0.27 to 1.10), below the published minimal clinically important difference for POEM of 3 points. The groups did not differ in secondary outcomes, economic outcomes, or adverse effects.

Conclusions This trial found no evidence of clinical benefit from including emollient bath additives in the standard management of eczema in children. Further research is needed into optimal regimens for leave-on emollient and soap substitutes.

Trial registration Current Controlled Trials ISRCTN84102309.

Reference: BMJ 2018;361:k1332

Anticholinergic drugs and risk of dementia: case-control study

Objectives To estimate the association between the duration and level of exposure to different classes of anticholinergic drugs and subsequent incident dementia.

Design Case-control study.

Setting General practices in the UK contributing to the Clinical Practice Research Datalink.

Participants 40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia.

Interventions Daily defined doses of anticholinergic drugs coded using the Anticholinergic Cognitive Burden (ACB) scale, in total and grouped by subclass, prescribed 4-20 years before a diagnosis of dementia.

Main outcome measures Odds ratios for incident dementia, adjusted for a range of demographic and health related covariates.

Results 14 453 (35%) cases and 86 403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was associated with an increasing average ACB score. When considered by drug class, gastrointestinal drugs with an ACB score of 3 were not distinctively linked to dementia. The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3. This result was also observed for exposure 15-20 years before a diagnosis.

Conclusions A robust association between some classes of anticholinergic drugs and future dementia incidence was observed. This could be caused by a class specific effect, or by drugs being used for very early symptoms of dementia. Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure.

Trial registration Registered to the European Union electronic Register of Post-Authorisation Studies EUPAS8705.

Reference: BMJ 2018;361:k1315

n−3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease

BACKGROUND

Dry eye disease is a common chronic condition that is characterized by ocular discomfort and visual disturbances that decrease quality of life. Many clinicians recommend the use of supplements of n−3 fatty acids (often called omega-3 fatty acids) to relieve symptoms.

METHODS

In a multicenter, double-blind clinical trial, we randomly assigned patients with moderate-to-severe dry eye disease to receive a daily oral dose of 3000 mg of fish-derived n−3 eicosapentaenoic and docosahexaenoic acids (active supplement group) or an olive oil placebo (placebo group). The primary outcome was the mean change from baseline in the score on the Ocular Surface Disease Index (OSDI; scores range from 0 to 100, with higher scores indicating greater symptom severity), which was based on the mean of scores obtained at 6 and 12 months. Secondary outcomes included mean changes per eye in the conjunctival staining score (ranging from 0 to 6) and the corneal staining score (ranging from 0 to 15), with higher scores indicating more severe damage to the ocular surface, as well as mean changes in the tear break-up time (seconds between a blink and gaps in the tear film) and the result on Schirmer’s test (length of wetting of paper strips placed on the lower eyelid), with lower values indicating more severe signs.

RESULTS

A total of 349 patients were assigned to the active supplement group and 186 to the placebo group; the primary analysis included 329 and 170 patients, respectively. The mean change in the OSDI score was not significantly different between the active supplement group and the placebo group (−13.9 points and −12.5 points, respectively; mean difference in change after imputation of missing data, −1.9 points; 95% confidence interval [CI], −5.0 to 1.1; P=0.21). This result was consistent across prespecified subgroups. There were no significant differences between the active supplement group and the placebo group in mean changes from baseline in the conjunctival staining score (mean difference in change, 0.0 points; 95% CI, −0.2 to 0.1), corneal staining score (0.1 point; 95% CI, −0.2 to 0.4), tear break-up time (0.2 seconds; 95% CI, −0.1 to 0.5), and result on Schirmer’s test (0.0 mm; 95% CI, −0.8 to 0.9). At 12 months, the rate of adherence to treatment in the active supplement group was 85.2%, according to the level of n−3 fatty acids in red cells. Rates of adverse events were similar in the two trial groups.

CONCLUSIONS

Among patients with dry eye disease, those who were randomly assigned to receive supplements containing 3000 mg of n−3 fatty acids for 12 months did not have significantly better outcomes than those who were assigned to receive placebo. (Funded by the National Eye Institute, National Institutes of Health; DREAM ClinicalTrials.gov number, NCT02128763.)

Reference: N Engl J Med 2018; 378:1681-1690

Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD

BACKGROUND

The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β2-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid–LABA or LAMA–LABA), are uncertain.

METHODS

In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate–vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium–vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment.

RESULTS

The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate–vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium–vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium–vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium–vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium–vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001).

CONCLUSIONS

Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate–vilanterol or umeclidinium–vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium–vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513.)

Reference: N Engl J Med 2018; 378:1671-1680

Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women

Question  What is the effect of 5-day nitrofurantoin, compared with single-dose fosfomycin, on clinical resolution of uncomplicated lower urinary tract infection (UTI) in women?

Findings  In this randomized clinical trial that included 513 women with uncomplicated UTI, clinical resolution at 28 days occurred in 70% of patients in the nitrofurantoin group vs 58% of patients in the fosfomycin group, a statistically significant difference.

Meaning  Five-day nitrofurantoin may be a better alternative to single-dose fosfomycin for treating uncomplicated UTI in women.

Reference: JAMA. 2018;319(17):1781-1789.