Matthew B. Stanbrook

Azithromycin reduced exacerbations and improved QoL in symptomatic asthma despite inhaled maintenance therapy

Question In patients who have symptomatic asthma despite inhaled maintenance therapy, does azithromycin reduce exacerbations and improve quality of life (QoL)? Methods Design Randomized placebo-controlled trial. Australian and New Zealand Clinical Trials Registry ACTRN12609000197235. Allocation Concealed.* Blinding Blinded* (patients, clinicians, investigators, and research staff). Follow-up period 52 weeks. Setting 8 clinical centers in Australia. Patients 420 adults 18 years of age (median age 60 y, 61% women) who had symptomatic asthma (Asthma Control Questionnaire [ACQ6] score 0.75) despite use of maintenance inhaled corticosteroids or long-acting bronchodilators, and remained stable (change in ACQ6 score <0.5) after completion of a 2-week optimized asthma treatment run-in with >80% adherence. Exclusion criteria included exacerbations, infections, or changes in maintenance medication in the past 4 weeks; current smoking; former smoking of >10 pack-y and diffusing capacity for carbon monoxide <70% predicted; hearing impairment; or abnormally prolonged QTc interval. Intervention Oral azithromycin, 500 mg 3 times/wk (n =213), or placebo (n =207), added to maintenance controller therapy for 48 weeks. Outcomes Severe and moderate asthma exacerbations and asthma QoL (Asthma Quality of Life Questionnaire [AQLQ]) at 48 weeks. Secondary outcomes included azithromycin-resistant pathogens in sputum, adverse events, and treatment discontinuation due to adverse events. Patient follow-up 80% (intention-to-treat analysis). Main results Azithromycin reduced severe and moderate exacerbations and improved asthma-related QoL (Table). The improvement in QoL from baseline reached the minimal important difference of 0.5 units in the symptoms domain but not the activity, emotions, or environment domains. Azithromycin increased risk for diarrhea (Table) but not azithromycin-resistant pathogens in sputum (Table) (based on 81 patients), other treatment-related adverse events, serious adverse events, or treatment discontinuation due to adverse events. Conclusion In patients who have symptomatic asthma despite inhaled maintenance therapy, azithromycin reduced exacerbations and improved quality of life. Azithromycin vs placebo in adults who have symptomatic asthma despite inhaled maintenance therapy Outcomes Events/person-y RRR (95% CI) NNT (CI) Azithromycin Placebo Exacerbations (severe and moderate) 1.07 1.86 25% (10 to 38) 7 (5 to 17) Mean scores Adjusted mean difference between groups (CI) Asthma-related quality of life (AQLQ) at 48 wk 5.73 5.55 0.36 (0.21 to 0.52) Event rates RRI (CI) NNH (CI) Azithromycin-resistant pathogens in sputum 49% 29% 71% (3 to 206) Not significant Diarrhea 34% 19% 79% (28 to 152) 7 (5 to 16) AQLQ = Asthma Quality of Life Questionnaire; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from data in article. Score range 1 to 7, higher scores indicate better quality of life (score information obtained from www.thoracic.org/members/assemblies/assemblies/srn/questionaires/aqlq.php). Positive between-group difference favors azithromycin. Assessed in 81 patients. Commentary Azithromycin is known to reduce exacerbations in selected patients with chronic obstructive pulmonary disease (COPD) (1). The randomized controlled trial by Gibson and colleagues provides the first clear evidence that azithromycin confers similar benefits in asthma that is inadequately controlled with first-line therapies. The adjusted mean difference between groups in AQLQ score, while statistically significant, is smaller than the established minimal clinically important difference of 0.5 (2), suggesting that the average patient did not experience an important QoL benefit with azithromycin. The reduction in exacerbations is far more relevant, as exacerbations can be life-threatening and place an important burden on both patients and the health care system. Azithromycin also increased the risk for diarrhea, but this was rarely severe enough to result in study withdrawal and would be expected to resolve promptly with treatment cessation. Although azithromycin was not observed to produce significant antimicrobial resistance, the trial was too small and too brief to assess this adequately. Because chronic bacterial airway infection is not a typical feature of asthma, potential antimicrobial resistance might be less consequential to patients with asthma than to patients with COPD or bronchiectasis, in whom azithromycin is already indicated. However, the established population risk for increasing antimicrobial resistance in the community with more widespread long-term azithromycin use (1) must also be considered. Most patients in this trial received high-dose inhaled corticosteroids, and nearly all received a long-acting -agonist. However, only a few received a long-acting muscarinic antagonist or a leukotriene modifier and none received a biologic. Any of these agents would be a valid alternative to adding azithromycin in this context. Head-to-head trials among these agents are needed.

In symptomatic COPD, once-daily triple vs dual therapy reduced moderate or severe exacerbations at 1 year

Question In patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations, does triple vs dual therapy reduce moderate or severe exacerbations? Methods Design Randomized controlled trial (RCT) (Informing the Pathway of COPD Treatment [IMPACT] trial). ClinicalTrials.gov NCT02164513. Allocation Concealed.* Blinding Blinded* (patients, investigators, test interpreters, and adjudicators for serious adverse events and deaths). Follow-up period 52 weeks (treatment period) plus 1 week for safety follow-up. Setting Centers in 37 countries. Patients 10367 patients 40 years of age (mean age 65 y, 66% men, mean COPD Assessment Test [CAT] score 20.1 out of 40) with symptomatic COPD (CAT score 10), and either FEV1 <50% of predicted normal with 1 moderate or severe exacerbation in the past year or FEV1 50% to 80% of predicted normal with 2 moderate or 1 severe exacerbations in the past year. Intervention Triple therapy with fluticasone furoate, 100 g, umeclidinium, 62.5 g, and vilanterol, 25 g (n =4155); or dual therapy with fluticasone furoate plus vilanterol (n =4139) or umeclidinium plus vilanterol (n =2073). Each therapy was taken in a single Ellipta inhaler once daily. Outcomes Primary outcome was annual rate of moderate (needing antibiotic or systemic glucocorticoid treatment) or severe (leading to hospitalization or death) exacerbations during treatment with triple therapy compared with each dual therapy. Other outcomes included severe exacerbations and all-cause mortality. Pneumonia events were reported. Patient follow-up 88% completed the trial (77% on treatment). 99.9% were included in the intention-to-treat analysis. Main results The main results are in the Table. Conclusion In chronic obstructive pulmonary disease, triple (fluticasone furoate, umeclidinium, and vilanterol) vs dual (vilanterol plus either fluticasone furoate or umeclidinium) therapy reduced moderate or severe exacerbations at 1 year. Fluticasone furoate, umeclidinium, and vilanterol (triple therapy) vs either fluticasone furoatevilanterol or umeclidiniumvilanterol in COPD Outcomes Events per patient-y At 1 y Triple therapy Fluticasonevilanterol Umeclidiniumvilanterol Rate ratio (95% CI) Moderate or severe exacerbations during treatment 0.91 1.07 0.85 (0.80 to 0.90) 0.91 1.21 0.75 (0.70 to 0.81) Severe exacerbations during treatment 0.13 0.15 0.87 (0.76 to 1.01) 0.13 0.19 0.66 (0.56 to 0.78) Events per 1000 patient-y Hazard ratio (CI) Clinician-diagnosed pneumonia 96 97 1.02 (0.87 to 1.19) 96 61 1.53 (1.22 to 1.92) Event rates (% patients) RRR (CI) NNT (CI) All-cause mortality (on or off treatment) 2.14% 2.35% 10% (20 to 33) Not significant 2.14% 2.90% 29% (1 to 49) 121 (71 to 3450) COPD = chronic obstructive pulmonary disease; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from event rates and hazard ratios in article supplement. Fluticasone furoatevilanterol vs umeclidiniumvilanterol: hazard ratio 0.79, CI 0.58 to 1.10. Commentary The IMPACT trial was designed to determine optimal drug therapy for COPD patients with both frequent exacerbations and more severe symptoms (group D in the international GOLD classification) (1). The finding that triple therapy achieved the best outcomes validates current guidelines and usual clinical practice for this most severe COPD subgroup. However, the reduction in mortality should be regarded with skepticism, as the larger SUMMIT trial failed to show that fluticasonevilanterol reduced mortality compared with placebo (2). As a comparative efficacy trial and 1 of the largest RCTs ever done in COPD, IMPACTs inclusion criteria were appropriately broad. However, because the study run-in period kept patients on their usual therapy, observed differences between groups might have arisen from adding or withdrawing medication (or both). The authors did not report results according to baseline treatment but did report that benefits of triple therapy over umeclidiniumvilanterol were seen particularly among patients with higher eosinophil levels, supporting eosinophils as a marker of steroid responsiveness in COPD. For symptomatic patients with infrequent exacerbations, IMPACTs findings create controversy: Although triple therapy again did best in this subgroup, fluticasonevilanterol produced a similar exacerbation rate to umeclidiniumvilanterol, which contradicts the previous FLAME trial (3). It is unclear whether this discrepancy arises from differences between the trials in specific medications, baseline therapies, or other confounders. Until this is sorted out, starting with dual rather than triple therapy in such patients may be justified based on safety, simplicity, and cost.

As-needed budesonide–formoterol better controlled mild asthma vs terbutaline, but maintenance budesonide was better

Question In patients with mild asthma, what is the efficacy of as-needed budesonideformoterol vs as-needed terbutaline or maintenance budesonide? Methods Design Randomized controlled trial (Symbicort Given as Needed in Mild Asthma [SYGMA] 1). ClinicalTrials.gov NCT02149199. Allocation Concealed.* Blinding Blinded* (patients, clinicians, and outcome adjudicators). Follow-up period 52 weeks. Setting 262 clinical centers in 18 countries/regions. Patients 3849 patients 12 years of age (mean age 40 y, 61% girls and women) who had a confirmed clinical diagnosis of asthma for 6 months, needed Global Initiative for Asthma 2012 criteria (GINA) step 2 treatment, and successfully completed a run-in period. Exclusion criteria included use of any -blocking agent; use of oral, rectal, or parenteral glucocorticoids in the past 30 days; worsening asthma that required a change in treatment in the past 30 days; 10 pack-year smoking history; or history of life-threatening asthma. Intervention As-needed budesonideformoterol, 200 g6 g, plus twice-daily placebo (n =1279); as-needed terbutaline, 0.5 mg, plus twice-daily placebo (n =1280); or maintenance budesonide, 200 g twice daily, plus as-needed terbutaline, 0.5 mg (n =1290). Outcomes Weeks with well-controlled asthma (no nighttime awakenings due to asthma; no additional inhaled and/or systemic glucocorticoid treatment due to asthma; and 2 or more of 2 d with a daily asthma symptom score >1, 2 d of as-needed medication use, up to 4 occasions/wk, or morning PEF 80% predicted every day). Secondary outcomes included severe exacerbations, time to first severe exacerbation, and adverse events. The study used hierarchical testing to assess the superiority of as-needed budesonideformoterol over as-needed terbutaline and its noninferiority to maintenance budesonide (prespecified noninferiority limit of 0.8 [2-sided 95% CI of the odds ratio]). Patient follow-up 87% completed the trial. Main results As-needed budesonideformoterol, as-needed terbutaline, and maintenance budesonide groups used a mean 99, 23, and 323 g of daily inhaled glucocorticoids, respectively, including open-label glucocorticoids. Results for weeks with well-controlled asthma and severe exacerbations are in the Table. As-needed budesonideformoterol prolonged the time to first severe exacerbation vs as-needed terbutaline (hazard ratio [HR] 0.44, 95% CI 0.33 to 0.58) but did not differ from maintenance budesonide (HR 0.90, CI 0.65 to 1.24). The as-needed terbutaline group (43%) had an increased risk for adverse events vs the as-needed budesonideformoterol (38%) or maintenance budesonide (40%) groups (P <0.05). Conclusions In patients with mild asthma, as-needed budesonideformoterol controlled symptoms better than as-needed terbutaline but not as well as maintenance budesonide plus as-needed terbutaline. Severe exacerbations for the 2 budesonide regimens were similar and lower than those for terbutaline. As-needed budesonideformoterol vs as-needed terbutaline or maintenance budesonide in mild asthma Outcomes Comparators Proportion of wk Odds ratio (95% CI) at 1 y Weeks with well-controlled asthma As-needed terbutaline 34% vs 31% 1.14 (1.00 to 1.30) Maintenance budesonide 34% vs 44% 0.64 (0.57 to 0.73) Annualized rates Rate ratio (CI) at 1 y Severe exacerbations As-needed terbutaline 0.07 vs 0.20 0.36 (0.27 to 0.49) Maintenance budesonide 0.07 vs 0.09 0.83 (0.59 to 1.16) CI defined in Glossary. P =0.046. Criterion for noninferiority was not met because lower limit of the 2-sided 95% CI of the odds ratio for as-needed budesonideformoterol vs maintenance budesonide was <0.8. Commentary Because formoterol is a rapid-acting and long-acting bronchodilator, budesonideformoterol can be used as an as-needed reliever in asthma. Previous studies, mostly in moderate to severe asthma, have shown substantial reductions in severe exacerbations when budesonideformoterol is used as both a regular maintenance inhaler and an as-needed reliever inhaler, compared with a maintenance inhaler with a separate short-acting -agonist reliever inhaler (1). The SYGMA 1 and SYGMA 2 trials provide evidence on whether as-needed budesonideformoterol might allow patients with mild asthma todispense with a regular maintenance inhaler all together. The answer may depend on ones perspective. Asthma causes ongoing airway inflammation in the absence of antiinflammatory treatment, even while patients are asymptomatic. That as-needed budesonideformoterol (which contains an inhaled steroid) was superior to as-needed terbutaline (which has no effect on inflammation) is therefore unsurprising, but it also achieved less asthma control than maintenance budesonide, which is concerning. Long-term, uncontrolled inflammation may lead to airway remodeling and fixed obstruction, which is an established risk factor in persons who do not use a maintenance inhaler (2). For patients and clinicians who place greater value on optimizing day-to-day asthma control and avoiding airway remodeling, these results confirm regular use of inhaled steroids as the preferred strategy in mild asthma. However, both trials found that as-needed budesonideformoterol was noninferior to maintenance budesonide for severe exacerbations, the most important common clinical outcome in asthma. For patients and clinicians who place more value on the burden and cost of daily asthma medication use and less value on day-to-day symptom avoidance, as-needed budesonideformoterol may be an acceptable strategy that will suffice to avoid serious short-term consequences. Of crucial importance, the results of the SYGMA trials apply only to patients with mild persistent asthma (those who can achieve control with low-dose inhaled steroids alone, GINA step 2) (2). Patients with moderate to severe asthma using as-needed budesonideformoterol must also use it as regular maintenance therapy. Patients with more severe asthma should be dissuaded from misinterpreting the findings of the SYGMA trials as support to drop their maintenance inhaler. Also, as patients in these trials were followed closely and had relatively good adherence to the maintenance inhaler, outcomes with as-needed budesonideformoterol might not be as good in real-world practice. The SYGMA trials were motivated by knowledge that asthma patients routinely do not optimally adhere to their medications (3). These results provide a basis for clinicians to have open conversations with patients with mild asthma about the risks and benefits of a regular maintenance inhaler and to make choices together in keeping with patients values and preferences.

In COPD, new use of long-acting bronchodilators was linked to CV events at ≤ 30 days, but not > 30 days

Question In patients with chronic obstructive pulmonary disease (COPD), do long-acting 2-agonists (LABAs) or long-acting muscarinic antagonists (LAMAs) increase risk for cardiovascular (CV) events? Methods Design Nested casecontrol study using data from the Taiwan National Health Insurance Research Database, which includes medical and pharmacy claims from all medical settings. Setting Taiwan. Patients The base cohort included 284220 patients 40 years of age (mean age 71 y, 69% men) who had International Classification of Diseases, Ninth Revision, (ICD-9) codes for 1 inpatient visit or 2 outpatient visits for COPD in a single year between 2008 and Jun 2011, and 1 prescription for COPD medication at each visit (cohort entry date = date of first outpatient visit or hospital discharge for COPD). Exclusion criteria were lack of continuous insurance coverage or use of LABAs or LAMAS in the year before the cohort entry date. From the base cohort, 37719 cases had a CV event at a mean follow-up of 2 years (index date = first CV event date) and were individually matched with up to 4 randomly selected controls (n =146139) using risk-set sampling. Matching was based on cohort entry date and a regression-based disease risk score, estimated for each patient using multiple covariates. An additional 763 cases without a corresponding control were excluded. Risk factors Use of LABAs or LAMAs 1 year before the index date (current use = 30 d, recent use =31 to 90 d, past use =91 to 180 d, and remote use = >180 d; new use = current use plus no use at 31 to 365 d; prevalent use = current use plus any use at 31 to 365 d). Outcomes CV events (coronary heart disease, cardiac arrhythmia, heart failure, or ischemic stroke) based on ICD-9-Clinical Modification primary diagnosis codes for inpatient or emergency department visits. Main results 16% of cases and 15% of controls used any LABAs or LAMAs in the year before the index date. Associations between current LABA or LAMA use and CV events are shown in the Table. Recent, past, or remote use of LABAs or LAMAs were not linked to increased risk for CV events (data not shown). Conclusions In chronic obstructive pulmonary disease, new use of long-acting 2-agonists or long-acting muscarinic antagonists was linked to increased risk for cardiovascular events 30 days after initiation. The drugs were not linked to events occurring >30 days after initiation. Associations between current use vs nonuse of LABAs or LAMAs and CV events in chronic obstructive pulmonary disease* LABA or LAMA exposure Drugs Adjusted odds ratio (95% CI) for CV events Current use LABA 1.06 (0.99 to 1.12) LAMA 1.00 (0.92 to 1.10) LABA + LAMA 1.16 (1.05 to 1.28) Current new use LABA 1.50 (1.35 to 1.67) LAMA 1.52 (1.28 to 1.80) LABA + LAMA 2.03 (1.42 to 2.91) Current prevalent use LABA 0.91 (0.85 to 0.98) LAMA 0.88 (0.79 to 0.98) LABA + LAMA 1.11 (1.00 to 1.23) *CV = cardiovascular; LABA = long-acting 2-agonist; LAMA = long-acting muscarinic antagonist; other abbreviations defined in Glossary. Current use = 30 d before CV event date (index date) in cases or matched index date in controls. New use = current use and nonuse at 31 to 365 d before index date; prevalent use = current use and any use at 31 to 365 d. Adjusted for covariates with prespecified baseline differences. Odds ratio >1 indicates greater risk for CV events with the drugs; odds ratio <1 indicates less risk for CV events with the drugs. Commentary Because LABAs and LAMAs by definition act on the autonomic nervous system, it is plausible that they could increase CV events, yet most randomized controlled trials (RCTs) of these agents have not shown such increases (1). These RCTs are prone to healthy volunteer bias, and many of them excluded patients with known CV disease; therefore, the large, population-based, observational study by Wang and colleagues provides a valuable real-world perspective on this question. Unfortunately, the main findings are probably an artifact of residual confounding by indication, despite rigorous methodologic efforts and sensitivity analyses to try to address this problem. Patients with COPD typically start a LABA or LAMA when their disease is unstable, based on symptoms, exacerbations, or a decrease in lung functionall of which are accepted indications for therapy (2). Wang and colleagues had no data on symptoms or lung function and adjusted for frequency, but not recency, of exacerbations. Therefore, COPD instability, rather than the LABA or LAMA given in response, was probably the direct cause of the CV events observed. Moreover, the reversal in direction of the association over time seems biologically implausible; the increased odds of CV events with new use, but decreased odds with prevalent use, further suggest confounding. Notwithstanding the above, the association of dual LABALAMA use with an increased odds of CV events warrants greater attention; dual use showed a stronger association with CV events than either agent alone and was seen with both prevalent and new use in current users. This finding should be considered in the context of COPD guidelines that support dual LABALAMA therapy (2). COPD is a leading cause of morbidity and mortality, so the findings of Wang and colleagues should not dissuade clinicians from starting LABAs or LAMAs, the most effective COPD medications to date (2), when indicated. However, they should be vigilant for CV events when starting LABA or LAMA therapy, regardless of whether the drug or the disease is responsible.

Review: In COPD, injectable polyvalent pneumococcal vaccines reduce risk for community-acquired pneumonia.

Question In patients with chronic obstructive pulmonary disease (COPD), do injectable pneumococcal vaccines reduce risk for pneumonia? Review scope Included studies compared injectable pneumococcal vaccines (polysaccharide, conjugate, or other type) with control (placebo or no vaccine) or another pneumococcal vaccine in adults with COPD. Primary outcomes were pneumonia, all-cause and respiratory-related mortality, and use of health care. Other outcomes included acute COPD exacerbation. Review methods Cochrane Airways Specialized Register, MEDLINE, EMBASE/Excerpta Medica, CENTRAL, ClinicalTrials.gov, and World Health Organization trials portal, all to Nov 2016; trial databases of pneumococcal vaccine manufacturers; and reference lists were searched for randomized controlled trials (RCTs). 12 RCTs (n =2171, mean age 66 y, 67% men) met the inclusion criteria: 9 evaluated a 23-valent pneumococcal polysaccharide vaccine (PPV), 3 evaluated a 14-valent PPV, and 1 evaluated a 7-valent diphtheria-conjugated pneumococcal vaccine (PCV). 6 RCTs used no vaccination as control, 3 used placebo, 2 used influenza vaccine in both treatment and control groups, and 1 RCT compared 23-valent PPV with 7-valent PCV. 3 RCTs had adequate allocation concealment, 4 blinded patients and study staff, 2 blinded outcome assessors, and 6 adequately addressed incomplete outcome data. Main results Meta-analysis showed that PPV reduced community-acquired pneumonia and COPD exacerbations compared with placebo or no pneumococcal vaccine; groups did not differ for pneumococcal pneumonia, all-cause or respiratory-related mortality, or any-cause hospitalization (Table). In 1 RCT (n =181) with 48-month follow-up, 23-valent PPV and 7-valent PCV did not differ for community-acquired pneumonia (relative risk [RR] 1.01, 95% CI 0.44 to 2.31), all-cause mortality (RR 1.77, CI 0.54 to 5.84), any-cause hospitalization (RR 0.93, CI 0.58 to 1.50), or COPD exacerbation (RR 1.04, CI 0.76 to 1.41). Conclusion In chronic obstructive pulmonary disease, injectable polyvalent pneumococcal vaccines reduce risk for community-acquired pneumonia at 6 to 36 months. Pneumococcal polysaccharide vaccine (PPV) vs control (placebo or no pneumococcal vaccine) in patients with COPD* Outcomes Number of trials (n) Weighted event rates RRR (95% CI) NNT (CI) PPV Control Community-acquired pneumonia at 6 to 36 mo 6 (1372) 9.4% 14% 33% (9 to 51) 21 (15 to 74) Pneumococcal pneumonia at 6 to 36 mo 3 (1158) 0.3% 1.1% 66% (66 to 93) NS All-cause mortality at 12 to 48 mo 5 (1053) 17% 17% 0% (24 to 32) NS Any-cause hospitalization at 6 to 12 mo 3 (391) 6.5% 8.6% 18% (45 to 54) NS COPD exacerbation at 6 to 24 mo 4 (446) 48% 61% 18% (3 to 32) 8 (5 to 58) RRI (CI) NNH Cardiorespiratory mortality at 24 to 48 mo 3 (888) 10.4% 9.8% 6% (28 to 57) NS *COPD = chronic obstructive pulmonary disease; NS = not significant; other abbreviations defined in Glossary. Weighted event rates, NNT, and CI obtained from Summary of Findings table in the review. RRR, RRI, and CI calculated from risk ratios obtained from Cochrane RevMan file using a fixed-effect model. Commentary Rates of pneumococcal vaccination among patients with COPD have historically been low (1) but may have increased recently (2). The Cochrane meta-analysis by Walters and colleagues adds 5 new trials to the previous 2010 review (3) and confirms that pneumococcal vaccines, in particular the 23-valent PPV, reduce pneumonia risk. Although specific effects on pneumococcal pneumonia did not reach statistical significance, the pooled result probably reflects lack of powerthe control group incidence of pneumococcal pneumonia was only 1.1%. Pneumococcal vaccines would not plausibly have direct effects on the many other pathogens known to cause morbidity in COPD, so it is unsurprising that no effects were found on all-cause hospitalizations or mortality. However, a key novel finding in the review is the significant reduction in COPD exacerbations with pneumococcal vaccination, with an observed relative risk similar in magnitude to that seen with inhaled medications routinely prescribed in COPD (4). This substantiates the important role of pneumococcal infections in COPD exacerbations. Conjugate vaccines stimulate both B-cell and T-cell responses and thus may be more immunogenic than polysaccharide vaccines, but the review found only 1 RCT of a PCV in COPD, with a PPV comparison group. More active-comparison RCTs of PCV vs PPV are needed.

Adding salmeterol to fluticasone did not increase serious asthma events and reduced exacerbations

Question In adolescents and adults with moderate to severe asthma, does adding salmeterol to fluticasone affect risks for serious asthma events or exacerbations? Methods Design Randomized controlled trial (RCT) (AUSTRI). ClinicalTrials.gov NCT01475721. Allocation Concealed.* Blinding Blinded* (patients, clinicians, investigators, outcome adjudicators, safety committee, {data collectors, and data analysts}). Patients and investigators were not blinded to fluticasone dose. Follow-up period 6 months after the first study drug dose or 7 days after the last dose, whichever was greater (approximately 26 wk). Setting 694 clinical centers in 33 countries. Patients 11751 adolescents and adults 12 years of age (mean age 43 y, 66% girls and women) who had asthma for 1 year, used daily asthma medication, and had been hospitalized or used systemic gluococorticoids for asthma exacerbations in the past 12 months but not the past 30 days. Exclusion criteria included life-threatening or unstable asthma or a smoking history of >10 pack-years. Intervention Fluticasonesalmeterol (n =5834) or fluticasone alone (n =5845), twice daily via a masked DISKUS dry-powder inhaler for 26 weeks. Fluticasone propionate was delivered at doses of 100 g, 250 g, or 500 g. Salmeterol dose was 50 g. Outcomes Serious asthma events (asthma-related deaths, intubations, or hospitalizations). Secondary outcomes included asthma exacerbations that required systemic glucocorticoids for 3 days, hospitalization, or emergency department visits with systemic glucocorticoid treatment. 11664 patients were needed to determine noninferiority of fluticasonesalmeterol vs fluticasone alone for serious asthma events based on an estimated fluticasone-alone event rate of 0.75% over 26 weeks (noninferiority margin for treatment hazard ratio was 2.0, 90% power, 1-sided =0.025). Patient follow-up 98% (intention-to-treat analysis). Main results Groups did not differ for serious asthma events (Table). The fluticasonesalmeterol group had fewer exacerbations than the fluticasone-alone group (Table). Conclusion In adolescents and adults with moderate to severe asthma, adding salmeterol to fluticasone did not increase risk for serious asthma events and reduced exacerbations. Fluticasonesalmeterol vs fluticasone alone in adolescents and adults with asthma Outcomes Event rates At 26 wk Fluticasonesalmeterol Fluticasone alone RRI (95% CI) NNH Serious asthma events 0.58% 0.56% 3% (36 to 66) Not significant RRR (CI) NNT (CI) Asthma exacerbations 8.2% 10.2% 20% (10 to 29) 49 (34 to 94) Abbreviations defined in Glossary. RRI, RRR, NNT, and CI calculated from fluticasone-alone event rates and hazard ratios in article. Deaths, intubations, or hospitalizations. Criterion for noninferiority was met because the upper CI of the hazard ratio (1.03, CI 0.64 to 1.66) was <2.0. Required systemic glucocorticoids for 3 d, hospitalization, or emergency department visits with systemic glucocorticoid treatment. Commentary There are long-standing concerns about whether regular use of inhaled -agonists has deleterious effects on asthma control. These concerns took on a new dimension when long-acting -agonists (LABAs), designed for use as daily control rather than as-needed relief, appeared on the market 2 decades ago. LABA monotherapy became contraindicated in asthma after 2 large studies observed increased asthma deaths with salmeterol (1, 2). Since then, a contentious unanswered question has been whether a LABA combined with an inhaled corticosteroid (ICS)the most effective evidence-based therapy for asthma patients suboptimally controlled with low- to medium-dose ICSs alone (3)mitigates its potential to cause fatal or life-threatening asthma events. To answer this question more definitively, the US Food and Drug Administration (FDA) required all LABA manufacturers to conduct new large safety trials (4). The 2 RCTs by Stempel and colleagues and the third by Peters and colleagues represent the main results of this initiative and probably provide the best evidence we will ever have on the safety of salmeterol and formoterol, which together account for most LABA-containing products dispensed for asthma. The trials were carefully designed through collaboration of manufacturers and the FDA. They accounted explicitly for differences in medication use and asthma control at baseline through algorithms that selected an individually appropriate ICS dose at the start of the trial and by stratifying randomization and statistical analysis. The finding in all 3 RCTs that LABA/ICS was noninferior to ICSs alone for serious asthma events should reassure most clinicians that LABA/ICS, when delivered as a fixed-dose combination to ensure equal adherence to both components, is safe in patients with moderate to severe asthma. These trials also confirm previous evidence that LABA/ICS is more effective than ICSs for preventing serious asthma exacerbations (5). Although the difference did not reach statistical significance in the VESTRI trial of children 4 to 11 years of age, this likely reflects lack of power as the hazard ratio was similar to those in the 2 larger trials in adolescents and adults. However, the clearer lack of benefit of LABA/ICS seen in children with asthma that was well-controlled with ICSs alone at baseline reinforces guideline recommendations that LABA/ICS should not be the first controller therapy in children (3). In contrast, findings that both adults and children who were well-controlled on LABA/ICS at baseline did worse if randomized to ICSs alone highlight the need for caution and more evidence regarding how and when to step down asthma therapy. Clinicians with residual concerns about LABA safety in asthma may find grounds for further skepticism in the large noninferiority margins used, which lack both scientific justification and face validity, especially the choice of a higher hazard ratio threshold in children than adults. Clearly, these margins were chosen pragmatically, solely to ensure trial feasibility. Also, all 3 trials excluded patients with a history of life-threatening asthma (defined as having required intubation or noninvasive ventilation)patients at the highest risk for the primary outcome. Thus, few severe asthma events were observed. A future study that pools the results of these and 2 other ongoing trials might define the risk for serious asthma events more precisely. Because the individual trials were not powered to evaluate subgroup effects, a pooled analysis might also help clarify LABA safety in subgroups believed to be at increased risk, such as African Americans. Pharmacogenomic substudies of these trials are planned to assess whether polymorphisms in the 2-adrenergic receptor affect LABA safety, as suggested previously (6).

Adding formoterol to budesonide did not increase serious asthma events and reduced exacerbations.

Question In adolescents and adults with asthma, does adding formoterol to budesonide affect risks for serious asthma events or exacerbations? Methods Design Randomized controlled trial (RCT). ClinicalTrials.gov NCT012444430. Allocation Concealed.* Blinding Blinded* ({patients, clinicians, data collectors, analysts}, and outcome adjudicators). Follow-up period 6 months after the first study drug dose or 7 days after the last dose, whichever was longer (approximately 26 wk). Setting 534 clinical centers in 25 countries. Patients 11693 adolescents and adults 12 years of age (mean age 43 y, 66% girls and women) who had asthma for 1 year, used daily asthma medication, and had 1 exacerbation in the past year but not the past 4 weeks. Exclusion criteria included unstable asthma in the past 7 days, >4 exacerbations or >2 hospitalizations for asthma in the past year, life-threatening asthma, or smoking history of >10 pack-years. Intervention Budesonideformoterol (n =5846) or budesonide alone (n =5847) twice daily for 26 weeks. Budesonideformoterol was administered through 2 actuations of an inhaler that delivered a total of 80 g budesonide (low dose) or 160 g budesonide (high dose), plus 4.5 g formoterol. Budesonide alone, 80 g or 160 g, was delivered by 2 actuations. Outcomes Serious asthma-related events (asthma-related deaths, intubations, or hospitalizations). Secondary outcomes included asthma exacerbations that required systemic glucocorticoids for 3 days, hospitalization, or emergency department visits with systemic glucocorticoid treatment. 11664 patients were needed to determine noninferiority of budesonideformoterol vs budesonide alone for serious asthma events based on an estimated budesonide-alone event rate of 0.75% over 26 weeks (noninferiority margin for treatment hazard ratio was 2.0, 90% power, =0.05). Patient follow-up 99% (intention-to-treat analysis). Main results Budesonideformoterol was noninferior to budesonide alone for serious asthma events but reduced risk for exacerbations (Table). Conclusion In adolescents and adults with asthma, adding formoterol to budesonide did not increase risk for serious asthma events and reduced exacerbations. Budesonideformoterol vs budesonide alone in adolescents and adults with asthma Outcomes Event rates At 26 wk Budesonide-formoterol Budesonide alone RRI (95% CI) NNH Serious asthma events 0.74% 0.68% 7% (30 to 65) Not significant RRR (CI) NNT (CI) Asthma exacerbations 9.2% 10.8% 16% (6 to 24) 59 (38 to 155) Abbreviations defined in Glossary. RRI, RRR, NNT, and CI provided by author. Deaths, intubations, or hospitalizations. Criterion for noninferiority was met because the upper CI of the hazard ratio (1.07, CI 0.70 to 1.65) was <2.0. Required systemic glucocorticoids for 3 d, asthma hospitalization, or emergency department visit with systemic glucocorticoid treatment. Commentary There are long-standing concerns about whether regular use of inhaled -agonists has deleterious effects on asthma control. These concerns took on a new dimension when long-acting -agonists (LABAs), designed for use as daily control rather than as-needed relief, appeared on the market 2 decades ago. LABA monotherapy became contraindicated in asthma after 2 large studies observed increased asthma deaths with salmeterol (1, 2). Since then, a contentious unanswered question has been whether a LABA combined with an inhaled corticosteroid (ICS)the most effective evidence-based therapy for asthma patients suboptimally controlled with low- to medium-dose ICSs alone (3)mitigates its potential to cause fatal or life-threatening asthma events. To answer this question more definitively, the US Food and Drug Administration (FDA) required all LABA manufacturers to conduct new large safety trials (4). The 2 RCTs by Stempel and colleagues and the third by Peters and colleagues represent the main results of this initiative and probably provide the best evidence we will ever have on the safety of salmeterol and formoterol, which together account for most LABA-containing products dispensed for asthma. The trials were carefully designed through collaboration of manufacturers and the FDA. They accounted explicitly for differences in medication use and asthma control at baseline through algorithms that selected an individually appropriate ICS dose at the start of the trial and by stratifying randomization and statistical analysis. The finding in all 3 RCTs that LABA/ICS was noninferior to ICSs alone for serious asthma events should reassure most clinicians that LABA/ICS, when delivered as a fixed-dose combination to ensure equal adherence to both components, is safe in patients with moderate to severe asthma. These trials also confirm previous evidence that LABA/ICS is more effective than ICSs for preventing serious asthma exacerbations (5). Although the difference did not reach statistical significance in the VESTRI trial of children 4 to 11 years of age, this likely reflects lack of power as the hazard ratio was similar to those in the 2 larger trials in adolescents and adults. However, the clearer lack of benefit of LABA/ICS seen in children with asthma that was well-controlled with ICSs alone at baseline reinforces guideline recommendations that LABA/ICS should not be the first controller therapy in children (3). In contrast, findings that both adults and children who were well-controlled on LABA/ICS at baseline did worse if randomized to ICSs alone highlight the need for caution and more evidence regarding how and when to step down asthma therapy. Clinicians with residual concerns about LABA safety in asthma may find grounds for further skepticism in the large noninferiority margins used, which lack both scientific justification and face validity, especially the choice of a higher hazard ratio threshold in children than adults. Clearly, these margins were chosen pragmatically, solely to ensure trial feasibility. Also, all 3 trials excluded patients with a history of life-threatening asthma (defined as having required intubation or noninvasive ventilation)patients at the highest risk for the primary outcome. Thus, few severe asthma events were observed. A future study that pools the results of these and 2 other ongoing trials might define the risk for serious asthma events more precisely. Because the individual trials were not powered to evaluate subgroup effects, a pooled analysis might also help clarify LABA safety in subgroups believed to be at increased risk, such as African Americans. Pharmacogenomic substudies of these trials are planned to assess whether polymorphisms in the 2-adrenergic receptor affect LABA safety, as suggested previously (6).