Corticosteroid

Corticosteroid use linked to development of adrenal insufficiency

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Patients using corticosteroids for various conditions may be at risk for developing adrenal insufficiency, according to recent findings.

In the systematic review and meta-analysis, Leonie H. A. Broerson, BSc, of Leiden University Medical Center in the Netherlands, and colleagues searched numerous databases in February 2014 for studies pertaining to adrenal insufficiency in adult corticosteroid users. Studies eligible for inclusion included randomized clinical trials, cohort studies and cross-sectional studies.

The researchers defined the meta-analysis’ main outcomes as the pooled percentages of patients with adrenal insufficiency after corticosteroid treatment, grouped by delivery method, disease, treatment dose and treatment duration. A random effects logistic regression model was used to pool percentages.

The researchers found that when stratified by administration method, the proportion of patients with adrenal insufficiency ranged from 4.2% for nasal administration to 52.2% for administration to the joints. When grouped by disease, the risk for adrenal insufficiency ranged from 6.8% for patients with asthma using inhalation corticosteroids only to 60% for hematologic cancers.

Risk for adrenal insufficiency ranged from 2.4% for low-dose to 21.4% for high dose when stratified by dose. When grouped by treatment duration, the risk for adrenal insufficiency ranged from 1.4% for 28 days’ duration to 27.4% for 1 years in patients with asthma only.

“In conclusion, this study demonstrates that all patients using corticosteroid therapy are at risk for adrenal insufficiency,” the researchers wrote. “This implicates that clinicians should 1) inform patients about the risk and symptoms of adrenal insufficiency, 2) consider testing patients after cessation of high-dose or long-term treatment with corticosteroids and 3) display a low threshold for testing, especially in those patients with nonspecific symptoms after cessation.” – by Jennifer Byrne

Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease.

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BACKGROUND: Current guidelines recommend that patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) should be treated with systemic corticosteroid for seven to 14 days. Intermittent systemic corticosteroid use is cumulatively associated with adverse effects such as osteoporosis, hyperglycaemia and muscle weakness. Shorter treatment could reduce adverse effects.
OBJECTIVES: To compare the efficacy of short-duration (seven or fewer days) and conventional longer-duration (longer than seven days) systemic corticosteroid treatment of adults with acute exacerbations of COPD. SEARCH
METHODS: Searches were carried out using the Cochrane Airways Group Specialised Register of Trials, MEDLINE and CENTRAL (Cochrane Central Register of Controlled Trials) up to June 2014 and ongoing trials registers up to July 2014.
SELECTION CRITERIA: Randomised controlled trials comparing different durations of systemic corticosteroid defined as short (i.e. seven or fewer days) or longer (i.e. longer than seven days). Other interventions-bronchodilators and antibiotics-were standardised. Studies with participants requiring assisted ventilation were excluded.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration.
MAIN RESULTS: Eight studies with 582 participants met the inclusion criteria, of which five studies conducted in hospitals with 519 participants (range 28 to 296) contributed to the meta-analysis. Mean ages of study participants were 65 to 73 years, the proportion of male participants varied (58% to 84%) and COPD was classified as severe or very severe. Corticosteroid treatment was given at equivalent daily doses for three to seven days for short-duration treatment and for 10 to 15 days for longer-duration treatment. Five studies administered oral prednisolone (30 mg in four, tapered in one), and two studies provided intravenous corticosteroid treatment. Studies contributing to the meta-analysis were at low risk of selection, performance, detection and attrition bias. In four studies we did not find a difference in risk of treatment failure between short-duration and longer-duration systemic corticosteroid treatment (n = 457; odds ratio (OR) 0.72, 95% confidence interval (CI) 0.36 to 1.46)), which was equivalent to 22 fewer per 1000 for short-duration treatment (95% CI 51 fewer to 34 more). No difference in risk of relapse (a new event) was observed between short-duration and longer-duration systemic corticosteroid treatment (n = 457; OR 1.04, 95% CI 0.70 to 1.56), which was equivalent to nine fewer per 1000 for short-duration treatment (95% CI 68 fewer to 100 more). Time to the next COPD exacerbation did not differ in one large study that was powered to detect non-inferiority and compared five days versus 14 days of systemic corticosteroid treatment (n = 311; hazard ratio 0.95, 95% CI 0.66 to 1.37). In five studies no difference in the likelihood of an adverse event was found between short-duration and longer-duration systemic corticosteroid treatment (n = 503; OR 0.89, 95% CI 0.46 to 1.69, or nine fewer per 1000 (95% CI 44 fewer to 51 more)). Length of hospital stay (n = 421; mean difference (MD) -0.61 days, 95% CI -1.51 to 0.28) and lung function at the end of treatment (n = 185; MD FEV1 -0.04 L; 95% CI -0.19 to 0.10) did not differ between short-duration and longer-duration treatment.
AUTHORS’ CONCLUSIONS: Information from a new large study has increased our confidence that five days of oral corticosteroids is likely to be sufficient for treatment of adults with acute exacerbations of COPD, and this review suggests that the likelihood is low that shorter courses of systemic corticosteroids (of around five days) lead to worse outcomes than are seen with longer (10 to 14 days) courses. We graded most available evidence as moderate in quality because of imprecision; further research may have an important impact on our confidence in the estimates of effect or may change the estimates. The studies in this review did not include people with mild or moderate COPD; further studies comparing short-duration systemic corticosteroid versus conventional longer-duration systemic corticosteroid for treatment of adults with acute exacerbations of COPD are required.

Inhaled corticosteroids in COPD and the risk of serious pneumonia

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Abstract

Background Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use.

Methods We formed a new-user cohort of patients with COPD treated during 1990–2005. Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia. A nested case–control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity.

Results The cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year). Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75). The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17). The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26).

Conclusions ICS use by patients with COPD increases the risk of serious pneumonia. The risk is particularly elevated and dose related with fluticasone. While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials.

Discussion

Using a large population-based cohort of over 160 000 patients with COPD followed for up to 18 years, we found that ICS use is associated with a significant 69% increase in the risk of serious pneumonia, requiring hospitalisation or fatal. This risk was particularly increased with fluticasone, with a doubling of the rate, and dose dependent with doses of 1000 μg of fluticasone per day associated with a 122% increase. The risk with budesonide was comparatively much lower with an increase of 17% and no dose–response effect. These elevated risks disappeared within a few months of stopping the use of ICS.

Systemic corticosteroids have been associated with increased risks of pneumonia in patients with rheumatoid arthritis.26 ,27 In these patients, a dose–response increase in the risk of pneumonia was seen with doses of prednisone as low as ≤5 mg/day (RR 1.4; 95% CI 1.1 to 1.6),26 and as low as 7.5 mg or less (RR 2.3; 95% CI 1.2 to 4.4).27 It is then not unexpected that high doses of ICS have similar effects on the incidence of pneumonia, as 1000 μg of inhaled fluticasone is estimated to be equivalent to 10 mg per day of prednisone with systemic effects evaluated by suppression of serum cortisol.7

Our findings confirm the observations of several randomised trials of varying durations and doses. The 2-year INSPIRE and 3-year TORCH trials both studied high doses of fluticasone (1000 μg per day) and found HRs of pneumonia of 1.94 (95% CI 1.19 to 3.17) and 1.64 (95% CI 1.33 to 2.02), respectively,3 ,4 ,13 ,14 A 1-year trial of fluticasone 1000 μg/day found a higher increase in the risk (RR 3.1; 95% CI 1.3 to 7.3; our calculation),15 which is consistent with our findings of a somewhat higher early risk. Our results confirm the subgroup analyses of the meta-analysis, suggesting that the risk is particularly elevated with high doses and start at short durations of use.12 With respect to the effect of dose, the two trials that evaluated a lower dose of fluticasone (500 μg per day) for 1 year also found a close to twofold higher incidence of pneumonia at 1 year with fluticasone.16–18This is also consistent with the dose–response curve from our study, which shows an increase in risk with lower doses and a RR of 1.6 at 500 μg/day of fluticasone.

The findings for budesonide confirm the pooled analysis of several trials of budesonide that found no increased risk of pneumonia over 1 year (RR 1.05; 95% CI 0·81 to 1·37),19 and a meta-analysis that suggests a lower risk with budesonide compared with fluticasone.20 Our finding of a more moderate 17% increase in the rate of serious pneumonia is concordant with these trial data. Moreover, the risk of pneumonia did not increase with the dose of budesonide. Nevertheless, a concern remains with budesonide as a recent 1-year trial in COPD found increases in pneumonia adverse events with daily doses of 640 μg (RR 2.3; 95% CI 1.2 to 4.7) and 320 μg (RR 1.7; 95% CI 0.8 to 3.6), equivalent to 400 μg and 200 μg of fluticasone, respectively.28 Since the fluticasone–salmeterol combination was approved and therefore promoted for COPD during the time period under study while the budesonide–formoterol combination was not, it remains possible that those receiving the budesonide combination were more likely to have asthma rather than COPD and be at lower risk of pneumonia compared with subjects receiving the fluticasone–salmeterol combination. Furthermore, since a higher dose formulation was only available for the fluticasone–salmeterol combination, patients with more severe disease may have been more likely to have received a combination therapy containing fluticasone rather than budesonide. Therefore, data on this question from countries where budesonide has a greater market share would be a valuable addition to this evidence.

There is good evidence supporting the effect of ICS on human pulmonary host defence, acting through several biological pathways, such as an inhibitory action on macrophage functions, a decrease in cytokine production and nitric oxide expression, which may lead to a failure to control infection.29 ,30 Although there have been no studies directly comparing the effects of fluticasone and budesonide on host defence, differences are likely related to their contrasting pharmacokinetic and pharmacodynamic properties. Fluticasone is known to be more potent (ie, greater effect on intracellular steroid receptors), more lipophilic and has a longer half life than budesonide.29Accordingly, fluticasone has a better penetration at the site of action and a more prolonged effect. It is therefore not surprising that a greater risk of oropharyngeal side effects is found with fluticasone compared with budesonide.31 While high potency and lipophilicity can be positive features allowing a lower dose to exert the desired effect, these characteristics may adversely affect drug safety. Indeed, a more prolonged corticosteroid effect in the lungs and greater pulmonary retention will facilitate the local immunosuppressive action.32 ,33 Budesonide enters the lungs with a lower lipophilicity, dissolves more quickly into pulmonary fluids, leading to a reduced local effect because of a more rapid cleavage and passage into the systemic circulation.30

This study has strengths and some limitations. The size of the population-based cohort of over 160 000 patients observed over 18 years permitted the identification of over 20 000 cases of serious pneumonia, allowing precise estimates of the risk associated with the different ICS at several doses. In this study, we defined serious pneumonia as a hospitalisation with a primary diagnosis of pneumonia or death from pneumonia, but did not have proof that the diagnosis was based on radiographic findings as these are not recorded in the RAMQ databases. However, it is most likely that as a primary inpatient diagnosis, it was in fact supported by a radiographic finding. To address confounding by COPD severity, we adjusted for the number of prescriptions for respiratory medications other than ICS, and for exacerbations as measured by prescriptions for oral corticosteroids, antibiotics, as well as prior hospitalisations for pneumonia and COPD exacerbation. Yet, residual confounding arising from unmeasured covariates can still be present. Of most concern is the possibility that budesonide may have been preferentially prescribed to patients with a lower risk of pneumonia, such as those with asthma or less severe COPD. In this specific study, however, our main results, adjusted for differences in severity, are consistent with those of several randomised trials which are inherently free of confounding, albeit less powerful with smaller study populations. Exposure to ICS was measured from dispensed prescriptions so that one must assume that the drugs were actually taken. However, not taking these medications would actually tend to underestimate the true risk increase. The definition of COPD used to identify the patients in our cohort was not based on a physician diagnosis of COPD or objective criteria for the diagnosis of COPD, but rather on including only subjects who started using respiratory medications at the age of 55 years or later and excluding subjects with a prior asthma hospitalisation or who used asthma-specific medications such as nedocromil, ketotifen, cromolyn or antileukotrienes. Nevertheless, our definition likely captured some patients with asthma. One can expect that this would reduce the estimate of risk of ICS since ICS do not appear to increase the risk of pneumonia in patients with asthma.34 Our sensitivity analysis within subjects previously hospitalised for COPD found practically the same differences in estimates of risk for fluticasone and budesonide.

The dose–response effect with fluticasone that we found on the incidence of serious pneumonia, sustained over a long time, is important in the risk–benefit balance for patients with COPD. While ICS are clearly effective for the treatment of asthma, their effectiveness in treating COPD is still controversial.1 ,2 The fact that ICS are now commonly combined in a single device with a long-acting bronchodilator, the latter recommended earlier in COPD, has resulted in ICS now being used by over 70% of patients with COPD.2 Moreover, these combined medications most often contain high doses of ICS, as high as 1000 μg of fluticasone per day.3 ,4 Consequently, the widespread use of ICS at higher doses in patients with COPD, along with the elevated incidence of pneumonia in this age group and their uncertain effectiveness, impact on the risk–benefit profile of ICS in COPD.

In conclusion, high and low doses of fluticasone in patients with COPD are associated with an important increase in the risk of serious pneumonia, while the risk with budesonide is comparatively low, even at high doses, though it needs further examination in light of recent data and the possibility that patients receiving budesonide are inherently at lower risk of pneumonia than those prescribed fluticasone. Further investigations into why the two popular ICS fluticasone and budesonide have such different effects on the risk of pneumonia are warranted.

Source: BMJ Thorax.

Fluticasone furoate and vilanterol for COPD.

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The Article by Mark Dransfield and colleagues1 reports replicate studies of the efficacy of fluticasone furoate and vilanterol on exacerbations in chronic obstructive pulmonary disease (COPD). The primary objective was to test the effect of a once-daily combination inhaler, so it is surprising that there was no comparator group of conventional twice-daily dosing. The distinctly modest improvement in comparison to the once-daily long-acting β agonist is certainly not greater, and perhaps even less than, that seen in several other studies using the twice-daily regimen. One cannot conclude that superior efficacy has been demonstrated for the once-daily dosing. Compliance may be improved with once-daily therapy but remains unproven for this class of drug.

Furthermore, as in many other studies of inhaled corticosteroid and long-acting β agonists, the significance of pre-study therapy is ignored. Over two thirds of patients in the studies of Dransfield and colleagues were taking an inhaled corticosteroid at study entry. Thus, those randomised to vilanterol alone underwent steroid withdrawal. Figure 4 in the Article shows that any difference in exacerbation rate occurs within 90 days of treatment initiation. The hypothesis that withdrawal of steroids increases exacerbations in COPD is well established.2 Re-analysis of the OPTIMAL study by Suissa and colleagues3 demonstrated no advantage for inhaled corticosteroids in addition to long-acting β agonists in steroid-naive patients, whereas those previously taking inhaled corticosteroids who were assigned to long-acting β agonist alone had a worse prognosis. We ask the authors to present the effects of fluticasone furoate and vilanterol on exacerbation rates stratified by inhaled corticosteroid pre-trial therapy. Until such evidence is forthcoming, we cannot rule out that any positive effects reported may be due to a simple artefact of trial design.

Even if anticipated, the confirmation of a significant excess of pneumonia with fluticasone furoate in a 1 year study is disappointing. This excess of pneumonia has been difficult to demonstrate with other inhaled corticosteroids4 and may be due to the greater lipophilicity and slower clearance of fluticasone, which with repeated dosing results in accumulation in the lung. Given this confirmation of fluticasone toxicity, should the position of high-dose fluticasone drugs be re-examined? In England, the market leader is fluticasone propionate (250 μg), salmeterol (25 μg) metred-dose inhaler, with sales of £170 million in 2011.5 Although unlicensed for COPD, its market position indicates confusion among doctors as to the diagnostic subtleties between severe asthma and COPD. We believe that the withdrawal of high-dose fluticasone preparations on safety grounds is now justified, and would also save patients and health-care providers a great deal of money.

JBM has received speaker fees and sponsorship to attend the ERS, ATS, BPS, and BTS conferences, and educational grants from pharmaceutical companies including Novartis, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Merck Sharp & Dohme, Pfizer, Amgen, Napp, Almirall, and Teva. AHM has received speaker fees and sponsorship to attend the ERS, ATS, and BPS conferences from pharmaceutical companies including Novartis, Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Proctor & Gamble, Almirall, AstraZeneca, Glenmark, and Philips Home Healthcare Solutions.

References

1 Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013; 1: 210-223. PubMed

2 Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur Respir J 2009; 34: 13-16. CrossRef | PubMed

3 Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008; 31:927-933. CrossRef | PubMed

4 Sin DD, Tashkin D, Zhang X, et al. Budesonide and the risk of pneumonia: a meta-analysis of individual patient data. Lancet2009; 374: 712-719. Summary | Full Text | PDF(174KB) | CrossRef | PubMed

5 Health and Social Care Information Centre, Prescribing and Primary Care. Prescription cost analysis—England.http://www.ic.nhs.uk/article/2021/WebsiteSearch?productid=5461&q=+prescriptions+cost+analysis+2011&sort=Relevance&size=10&page=1&area=both#top. (accessed May 10, 2013).

Source: Lancet

Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting β2 agonist: observational matched cohort study (PATHOS).

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Abstract

Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease (COPD) treated with two different fixed combinations of inhaled corticosteroid/long acting β2 agonist.

Design Observational retrospective pairwise cohort study matched (1:1) for propensity score.

Setting Primary care medical records data linked to Swedish hospital, drug, and cause of death registry data for years 1999-2009.

Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol.

Main outcome measures Yearly pneumonia event rates, admission to hospital related to pneumonia, and mortality.

Results 9893 patients were eligible for matching (2738 in the fluticasone/salmeterol group; 7155 in the budesonide/formoterol group), yielding two matched cohorts of 2734 patients each. In these patients, 2115 (39%) had at least one recorded episode of pneumonia during the study period, with 2746 episodes recorded during 19 170 patient years of follow up. Compared with budesonide/formoterol, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol: rate ratio 1.73 (95% confidence interval 1.57 to 1.90; P<0.001) and 1.74 (1.56 to 1.94; P<0.001), respectively. The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 (10.4 to 11.8) versus 6.4 (6.0 to 6.9) and the rate of admission to hospital was 7.4 (6.9 to 8.0) versus 4.3 (3.9 to 4.6). The mean duration of admissions related to pneumonia was similar for both groups, but mortality related to pneumonia was higher in the fluticasone/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths) (hazard ratio 1.76, 1.22 to 2.53; P=0.003). All cause mortality did not differ between the treatments (1.08, 0.93 to 1.14; P=0.59).

Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD.

Conclusions and future research

This observational matched cohort study indicated that there is an intraclass difference between inhaled corticosteroid/long acting β2 agonist regarding the risk of pneumonia and pneumonia related mortality in the treatment of patients with COPD. The higher risk of pneumonia in patients treated with fluticasone/salmeterol might be related to differences in immunosuppressant potency and pharmacokinetic and pharmacodynamic properties between budesonide and fluticasone. Whether other unknown risks of pneumonia that were not adequately controlled for in this matched cohort study contributed to our findings remains uncertain. The magnitude of the intraclass difference in pneumonia needs to be put in context with the benefits of each regimen in preventing exacerbations. Long term randomised controlled trials comparing fixed combinations of inhaled corticosteroid/long acting β2 agonist in COPD with respect to occurrence of pneumonia and exacerbations are, therefore, warranted.

 

What is already known on this topic

  • Pneumonia is a common complication of COPD, which is associated with considerable morbidity, mortality, and health costs
  • Treatment with inhaled corticosteroids and long acting β2 agonists (fixed dose combinations) can increase the risk of pneumonia in these patients, though it is not known if there is a variation in risk between different combinations
  • This observational matched cohort study indicated that there is an intraclass difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to risk of pneumonia and pneumonia related events in patients with COPD

What this study adds

 

Sourc: BMJ

COPD treatment: time to change our algorithm?

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For the past decade, clinicians have largely followed a set of similar algorithms for chronic obstructive pulmonary disease (COPD) therapy, initiating treatment with an inhaled longacting antimuscarinic (LAMA) and adding combination therapy with a longacting β agonist (LABA) plus an inhaled corticosteroid when symptom or exacerbation control is inadequate. This algorithm is also in accordance with the Global initiative for chronic Obstructive Lung Disease (GOLD) 2007 consensus statement.1 However, the GOLD 2013 consensus statement challenges clinicians to rethink this routine.2 A wide range of treatment options are proposed including LAMA/LABA dual therapy, which is recommended as a treatment alternative for group B (high symptoms/low risk), C (low symptoms/high risk), and D (high symptom/high risk) patients. However, few data have been available to support the efficacy of this combination therapy over single agent bronchodilator therapy. Good data already exist for the efficacy of LAMA monotherapy for symptom control and exacerbation reduction3 as well as for the efficacy of LABA monotherapy for symptom control,4 but scarce data have been available for whether dual agent therapy has additional benefit in terms of either symptom control or exacerbation reduction.

In The Lancet Respiratory Medicine, Jadwiga Wedzicha and colleagues5 present data from the SPARK study, a randomised, three-group, double-blind study in COPD comparing once-daily indacaterol plus glycopyrronium combination therapy (QVA149) versus glycopyrronium alone versus open-label tiotropium. The primary endpoint examined was superiority of QVA149 versus glycopyrronium in reducing the frequency of moderate to severe COPD exacerbations, with the comparison of QVA149 versus tiotropium as a major secondary endpoint. Inclusion criteria were post-bronchodilator forced expiratory volume in 1 s (FEV1) less than 50% and at least one exacerbation in the previous 12 months. This study showed a 12% reduction in the rate of moderate to severe exacerbations for QVA149 compared with glycopyrronium (rate ratio [RR] 0·88, 95% CI 0·77—0·99, p=0·038). The 10% reduction in moderate to severe exacerbations for QVA149 compared with tiotropium was not significant (RR 0·90, 95% CI 0·79—1·02, p=0·096). QVA149 also resulted in significantly higher trough FEV1 as compared to glycopyrronium (differences 70—80 mL, p<0·0001) and tiotropium (differences 60—80 mL, p<0·0001) and resulted in 8—9 unit improvements in St George’s Respiratory Questionnaire score (SGRQ) total score as opposed to 6 units with glycopyrronium and 5—6 units with tiotropium, both significant differences.

The real question is how these data should influence prescribing practices for COPD. These data support better lung function improvement, better symptom control, and greater exacerbation reduction with LAMA/LABA therapy as opposed to LAMA therapy alone in patients with severe to very severe disease. In reality, such patients are likely to be on some form of therapy before they progress to this level of disease severity. Hence for the patient already on LAMA therapy, the addition of a LABA, particularly if exacerbation reduction is a goal, as a next step in therapy is supported by these data.

These data must be interpreted in light of the fact that about 75% of patients were on concomitant inhaled corticosteroids, which has several implications. First, the magnitude of exacerbation reduction seen was 12%, which is arguably clinically significant but might have been attenuated owing to concomitant inhaled corticosteroid use. These results mirror the magnitude of reduction seen with tiotropium in the UPLIFT study,3 in which concomitant inhaled corticosteroid plus LABA therapy was allowed. Second, the high rates of concomitant inhaled corticosteroid use also mean that these data perhaps provide less support for the GOLD recommendation of LABA/LAMA as dual therapy for either groups C or D and perhaps provide greater support for triple therapy (addition of LABA to LAMA plus inhaled corticosteroids) for C and D patients.

In further thinking about how these data inform prescribing practices, one should also note that 22% of patients studied had two or more moderate or severe exacerbations in the previous year. Previous data suggest that group D patients who are judged to be at high risk by both FEV1 and exacerbation criteria are at even greater risk of moderate and severe exacerbations than are those meeting a single criterion, suggesting good efficacy in a relatively high risk population.6 On the other hand, another interesting finding of the study was that the greatest reduction was seen in mild exacerbations—15% with QVA149 compared with glycopyrronium and 16% compared with tiotropium—with mild exacerbations defined as an event with increase in symptoms but self-managed by the patient. Although exacerbation events requiring therapy are more frequently studied, the importance of untreated events should not be underestimated. Even events unreported to a health-care provider have been shown to be associated with significantly worse health status,7 which might explain the improvements in SGRQ score seen with QVA149 therapy.

Overall, these data support greater efficacy for dual bronchodilator therapy with QVA149 as compared with LAMA monotherapy. In view of the lack of data in the past, the use of combination LABA/LAMA therapy has not been embraced by medical practitioners for use in COPD, but these new data suggest dual therapy is an important therapeutic option when trying to maximise symptom improvement and exacerbation reduction.

Source: Lancet

 

Perioperative Steroids Do Not Increase Serious Bleeding After Tonsillectomy .

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Children undergoing tonsillectomy who receive perioperative corticosteroid therapy — as recommended by current guidelines to reduce postoperative nausea and vomiting — do not face increased risk for postoperative bleeding, according to a JAMA study.

In response to a study suggesting such steroid use increases hemorrhage after tonsillectomy, researchers randomized some 300 children to perioperative intravenous dexamethasone or placebo. During the 14 days after tonsillectomy, rates of bleeding that required hospitalization or surgical repair (so-called level II or III bleeds) did not differ between the groups.

Level I bleeds — defined as any reported bleeding event, regardless of clinical evidence — were more common with dexamethasone than with placebo (11 vs. 7 events). However, the authors point out that such events tended to be “nondescript and self-limited.” Level II and III bleeds, they say, “are a more reliable indicator for complications.”

Source: JAMA