Salmeterol Group Research Articles

New ways to repurpose salmeterol in an animal model of fibromyalgia.

Fibromyalgia (FM) is a syndrome of pervasive chronic pain accompanied by low mood, sleep disorders, and cognitive decline. The dysfunction of central pain processing systems along with neurotransmitter disturbances are possible contributing mechanisms. Genetic polymorphism of the 𝛽2 adrenergic receptors is reported in FM patients. It is reported that chronic β2 agonists administration is effective for neuropathic pain alleviation. No current information, however, exists on their potential to alleviate nociplastic pain, such as FM. Therefore, the purpose of the current study is to examine salmeterol's potential antiallodynic effects in experimentally produced FM and explore some of the possible contributing mechanisms. Thirty rats are allocated into three groups (n = 10): a normal group, a reserpine group that received reserpine (1 mg/kg; s.c.) for 3 days, and a reserpine + salmeterol group that received salmeterol (1 mg/kg; i.p.) for 21 consecutive days following last reserpine injection. Reserpine administration resulted in behavioral and biochemical changes consistent with FM, including thermal and mechanical hyperalgesia, depressive behavior, and motor incoordination. This is coupled with disturbed spinal monoamine levels, depressed cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, disturbed mitochondrial function/dynamics, and compromised blood-nerve barrier integrity. Treatment with salmeterol conceivably reversed these effects. β2 receptor agonists such as salmeterol could be regarded as a promising strategy for the management of FM.

A comparative study on safety profile and efficacy of salmeterol and tiotropium in COPD Patients

Aim and Objectives: The aim of the study is assess the safety profile and efficacy of salmeterol and Tiotropium in patients with COPD. The objective is to compare to evaluate the safety profile and efficacy of salmeterol and Tiotropium in patients with COPD. Methodology: This was a prospective observational study conducted at secondary care hospital in India. In our study, we have included a total of 50 patients who are divided in to two groups based on their treatment and follow-ups was done for 12 weeks. Results: Patients were divided into 2 equal groups to receive salmeterol and Tiotropium (25 subjects each). The mean FEV1 level at baseline was 63.72±3.0210 for Tiotropium group and 64.96±1.645 for Salmeterol group and the mean FEV1 level after 12 weeks of treatment was 72.12±1.423 for Tiotropium group and 70.68±1.973 for Salmeterol group. Tiotropium treatment were associated with significant decrease in FEV1 level from baseline to 12 weeks. (P*<0.05). Conclusion: In our study, by performing the study, we concluded that tiotropium used once daily, produced superior bronchodilation and reduced dyspnea in patients with COPD when compared with salmeterol. Patients treated with tiotropium also indicated more improvement in their symptoms than those who treated with salmeterol. Because of these advantages, tiotropium should be considered first-line treatment in patients with COPD. While performing the safety parameters for a drug, side effects of tiotropium are less when compared to salmeterol.

The stimulation and inhibition of beta-2 adrenergic receptor on the inflammatory responses of ovary and immune system in the aged laying hens

BackgroundOvarian chronic inflammation has been known to incidence in the laying hen mainly via increasing laying frequency and microbial infection, especially during late stage of production period. This study was aimed to evaluate beta-2 adrenergic agonist (Beta-2 Adrenergic Agonist, BAA) Salmeterol and beta blocker (Beta Blocker, BB) Propranolol on the gene expression of the ovarian pro- and anti-inflammatory mediators, inflammatory responses of immune system, ovarian functions and, hormones in the laying hens on the late stage of production period. Forty-eight White Leghorn hens aged 92 weeks were used for 4 weeks to be supplemented by Salmeterol and Propranolol. Ovulation rate and follicular growth were determined based on laying frequency and ovarian visual evaluation, respectively; the mRNA expressions of follicular beta-2 adrenergic receptor (Beta-2 Adrenergic Receptor, β2ADR), cyclooxygenases (Cyclooxygenases, COX) 1 and 2, and cytokines were measured by real-time PCR. The plasma concentration of ovarian hormones, cellular, and humoral immune responses were measured via ELISA, heterophil to lymphocyte ratio (Heterophil to Lymphocyte ratio, H:L), and sheep red blood cell (Sheep Red Blood Cell, SRBC) test, respectively.ResultsAs compared to control, both of BAA Salmeterol and BB Propranolol resulted in a significant decrease in the mRNA expression of β2ADR, cyclooxygenases, and pro- and anti-inflammatory cytokines (P < 0.01). A significant elevation was observed in the ovulation rate (P < 0.05), plasma estradiol content on both treated groups (P < 0.05), and the content of progesterone and was just significantly (P < 0.05) increased in Salmeterol group. H:L was reduced in BAA group (P < 0.05), and immunoglobulin (Ig) M was elevated in both treated hens, when compared to control. The results indicated that Salmeterol significantly increases body weight (P < 0.05).ConclusionThe stimulation and inhibition of beta-2 adrenergic signaling could reduce ovarian inflammatory condition in addition to enhancing laying efficiency in the aged laying hens.

Improved Sprint Performance With Inhaled Long-Acting β2-Agonists Combined With Resistance Exercise.

To investigate the impact of twice-daily inhalation of 100µg of salmeterol (SAL) or 12µg of formoterol (FOR) in addition to a strength- and power-training program over a 5-wk period on a 30-m sprint, strength, power, mood, stress, and skinfold thickness. In a randomized, single-blind study, 23 male and 15 female nonasthmatic, recreationally active individuals were recruited (mean [SD] age 26.3 [5.4]y, weight 76.2 [11.5]kg, height 176.9 [8.5]cm). Participants completed 3 standardized whole-body strength- and power-training sessions per week for 5wk during which they were assigned to an SAL, FOR, or placebo group. Participants used their inhaler twice per day as instructed and completed assessments of sprint, strength, and power at baseline and 1wk after cessation of the training program. The assessments included a 30-m sprint, vertical jump, 1-repetition-maximum (1RM) bench press, 1RM leg press, peak torque flexion and extension, anthropometric evaluation, and Rest-Q questionnaires. After 5 wk of strength and power training, 30-m sprint time reduced in the FOR (0.29 [0.11]s, P = .049) and SAL (0.35 [0.05]s, P = .040) groups compared with placebo (+0.01 [0.11]s). No significant change was found in other assessments of strength, mood, or skinfold thickness. When strength and power training are combined with the inhalation of FOR or SAL over a 5-wk period, moderately trained individuals experience an improvement in 30-m sprint performance.

AN ASSESSMENT OF TIME TO ONSET OF BRONCHODILATION FOLLOWING TREATMENT WITH NEBULIZED ARFORMOTEROL IN PATIENTS WITH COPD

SESSION TITLE: Wednesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM PURPOSE: Short and long-acting beta2-agonists are commonly utilized for the treatment of chronic obstructive pulmonary disease (COPD). Arformoterol tartrate (ARF; 15 μg twice daily [BID]) is a long-acting beta2-agonist (LABA) approved for the long-term maintenance treatment of bronchoconstriction in patients with COPD; ARF should not be used as rescue medication. ARF exhibits a rapid onset of action, producing significant bronchodilation and a long duration of effect. The time to onset of bronchodilation following treatment with nebulized ARF was assessed in COPD patients stratified by baseline forced expiratory volume in 1 second (FEV1) % predicted. METHODS: Data from two identical, 12-week, randomized Phase III trials (NCT00685841 and NCT00064402) evaluating improvement in airway function with ARF treatment in patients with COPD were pooled for analysis. Patients (n=1456; mean predicted FEV1=40.6% [standard deviation: 12.8]) received nebulized ARF 15 μg BID, 25 μg BID, or 50 μg once daily (QD), salmeterol 42 μg BID (using a metered dose inhaler), or placebo BID for 12 weeks. The time to onset was determined from serial spirometry assessments performed immediately and at 15 and 40 minutes, 1, 2, 3, 4, 5, 6, 8, 10, 12, 23, and 24 hours post-first dose. Time to onset of bronchodilation was defined as the time at which the linear interpolated value of FEV1 is equal to 12% change from baseline. The median time to onset, following administration of the first dose, was estimated using the Kaplan-Meier method. RESULTS: Across ARF treatment groups, time to onset of bronchodilation was quicker in the groups with the lowest baseline FEV1 % predicted. The median time to onset of bronchodilation for the approved ARF 15 μg BID dose, stratified by baseline FEV1 % predicted (<30, ≥30-<50, and ≥50), was 1.8, 3.6, and 42.2 minutes, respectively. The median time to onset was longer for placebo (122.1, 290.3, N/A) and salmeterol (14.6, 16.0, 43.7) groups by baseline FEV1 % predicted (<30, ≥30-<50, and ≥50, respectively) compared with ARF 15 μg BID. CONCLUSIONS: In this post-hoc analysis, median time to onset of bronchodilation in patients with COPD was shorter following treatment with nebulized ARF 15 μg BID than with placebo or salmeterol, regardless of baseline FEV1 % predicted. Notably, patients with COPD treated with nebulized ARF 15 μg BID demonstrated a rapid time to onset in patients with a baseline FEV1 % predicted <50%. CLINICAL IMPLICATIONS: Bronchodilators are essential in the management of COPD symptoms. These data highlight the rapid onset of bronchodilation observed with ARF 15 μg BID compared to placebo or salmeterol in all patients, independent of baseline disease severity. The observed differences between the clinically approved LABAs, ARF 15 ug BID and salmeterol 50 ug QD, may be due to dosing frequency, receptor uptake or mode of delivery. DISCLOSURES: Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/11/2019 by Thomas Goodin, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/12/2019 by Ayca Ozol-Godfrey, source=Admin input, value=Salary Employee relationship with Sunovion Pharmaceuticals Please note: >$100000 Added 03/13/2019 by Barry Price, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Inc. Please note: >$100000 Added 03/14/2019 by Shahin Sanjar, source=Web Response, value=Salary Employee relationship with Sunovion Pharmaceuticals Inc. Please note: $20001 - $100000 Added 03/11/2019 by Sanjay Sharma, source=Web Response, value=Salary Removed 03/11/2019 by Sanjay Sharma, source=Web Response Employee relationship with Sunovion Pharmaceuticals, Inc. Please note: >$100000 Added 03/11/2019 by Sanjay Sharma, source=Web Response, value=Salary

Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma

BackgroundLong-acting beta-agonists (LABAs) have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children.MethodsWe randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. The statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis.ResultsAmong the 6208 patients, 27 patients in the fluticasone–salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone–salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone–salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone–salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01).ConclusionsIn this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344.)

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone

BackgroundThe safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate.MethodsIn this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone–salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation.ResultsOf 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone–salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone–salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone–salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone–salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001).ConclusionsPatients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone–salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.)

Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials

In patients with severe asthma, tiotropium improves lung function and exacerbation risk when added to high-dose inhaled corticosteroids plus long-acting β2 agonists. We aimed to assess the safety and efficacy of tiotropium in patients with moderate asthma who were symptomatic despite treatment with medium-dose inhaled corticosteroids. We did two 24-week, replicate, randomised, double-blind, placebo-controlled, parallel-group, active-comparator trials at 233 sites in 14 countries. Eligible patients were aged 18-75 years with symptomatic asthma and a pre-bronchodilator forced expiratory volume in 1 s (FEV1) of 60-90% predicted despite use of medium-dose inhaled corticosteroids, and had never smoked or were ex-smokers for 1 year or more with 10 pack-years or less. Patients were randomly assigned (1:1:1:1), with computer-generated pseudorandom numbers, to receive once-daily tiotropium 5 μg or 2·5 μg, twice-daily salmeterol 50 μg, or placebo, while maintaining inhaled corticosteroids. Patients and study investigators were masked to treatment allocation. Prespecified co-primary endpoints, assessed at week 24 in the full analysis set, were peak FEV1 response, measured within the first 3 h after evening dosing; trough FEV1 response; and responder rate assessed according to the seven-question Asthma Control Questionnaire (ACQ-7). These studies are registered with ClinicalTrials.gov, numbers NCT01172808 and NCT01172821. Between Aug 24, 2010, and Nov 13, 2012, we randomly assigned 2103 patients to the tiotropium 5 μg group (n=519), the tiotropium 2·5 μg group (n=520), the salmeterol group (n=541), or the placebo group (n=523); 1972 (94%) patients completed the study. Peak and trough FEV1 responses were significantly greater with tiotropium and salmeterol than with placebo and were similar in both studies. With pooled data, difference versus placebo in peak FEV1 was 185 mL (95% CI 146-223) in the tiotropium 5 μg group, 223 mL (185-262) in the tiotropium 2·5 μg group, and 196 mL (158-234) in the salmeterol group (all p<0·0001); difference in trough FEV1 was 146 mL (95% CI 105-188), 180 mL (138-221), and 114 mL (73-155; all p<0·0001), respectively. There were more ACQ-7 responders in the tiotropium 5 μg (OR 1·32, 95% CI 1·02-1·71; p=0·035) and 2·5 μg (1·33, 1·03-1·72; p=0·031) groups, and the salmeterol group (1·46, 1·13-1·89; p=0·0039), than in the placebo group. 48 (2%) of 2100 patients had serious adverse events (tiotropium 5 μg n=11, tiotropium 2·5 μg n=12, salmeterol n=11, placebo n=14). Once-daily tiotropium add-on to medium-dose inhaled corticosteroids reduces airflow obstruction and improves asthma control in patients with moderate symptomatic asthma. Patterns of response with both tiotropium doses were similar to those of salmeterol, and all active compounds had good safety and tolerability. Tiotropium is a safe and effective bronchodilator, and an alternative to salmeterol in this patient population. Boehringer Ingelheim.

The Beta Agonist Lung Injury Trial Prevention. A Randomized Controlled Trial

Experimental studies suggest that pretreatment with β-agonists might prevent acute lung injury (ALI). To determine if in adult patients undergoing elective esophagectomy, perioperative treatment with inhaled β-agonists effects the development of early ALI. We conducted a randomized placebo-controlled trial in 12 UK centers (2008-2011). Adult patients undergoing elective esophagectomy were allocated to prerandomized, sequentially numbered treatment packs containing inhaled salmeterol (100 μg twice daily) or a matching placebo. Patients, clinicians, and researchers were masked to treatment allocation. The primary outcome was development of ALI within 72 hours of surgery. Secondary outcomes were ALI within 28 days, organ failure, adverse events, survival, and health-related quality of life. An exploratory substudy measured biomarkers of alveolar-capillary inflammation and injury. A total of 179 patients were randomized to salmeterol and 183 to placebo. Baseline characteristics were similar. Treatment with salmeterol did not prevent early lung injury (32 [19.2%] of 168 vs. 27 [16.0%] of 170; odds ratio [OR], 1.25; 95% confidence interval [CI], 0.71-2.22). There was no difference in organ failure, survival, or health-related quality of life. Adverse events were less frequent in the salmeterol group (55 vs. 70; OR, 0.63; 95% CI, 0.39-0.99), predominantly because of a lower number of pneumonia (7 vs. 17; OR, 0.39; 95% CI, 0.16-0.96). Salmeterol reduced some biomarkers of alveolar inflammation and epithelial injury. Perioperative treatment with inhaled salmeterol was well tolerated but did not prevent ALI. Clinical trial registered with International Standard Randomized Controlled Trial Register (ISRCTN47481946) and European Union database of randomized Controlled Trials (EudraCT 2007-004096-19).

Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial

The effect of β2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol. We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381. 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events. Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of β-adrenergic polymorphisms and their association with clinical features of COPD. Boehringer Ingelheim and Pfizer.

LABA monotherapy in asthma: an avoidable problem

Long-acting beta 2-agonists (LABAs) (or beta-adrenoceptor agonists) improve lung function and quality of life, and are recommended at step 3 of the national guidelines for the management of asthma.1 However, chronic exposure to LABAs can be associated with tolerance and reduced sensitivity to the bronchodilator effects of salbutamol raising concerns over their use in asthma.2 In 2006 a large randomised trial called SMART (Salmeterol Multi-Centre Asthma Research Trial) involving 26 355 patients randomised to either inhaled salmeterol or placebo in addition to their usual care was reported.3 This trial found that significantly more serious adverse events and asthma-related deaths occurred in the salmeterol group. This risk was potentially confined to patients treated with LABA monotherapy only, as regular use of inhaled corticosteroids (ICS) was limited. A review of available data by the Medicines and Healthcare products Regulatory Agency (MHRA) concluded that the benefits of LABA/ICS combination therapy outweigh any potential risks in asthma.4 For this reason, LABAs are currently recommended for the management of asthma in combination with an ICS only. In 2009 the British Thoracic Society/Scottish Intercollegiate Guideline Network (BTS/SIGN) national asthma guidelines recommended prescribing LABAs either as separate inhalers or in combination inhalers with ICS.5 However, in 2011 BTS/SIGN revised their guidelines …

Long term therapy and outcome of chronic obstructive pulmonary disease with or without co-morbidity: the TORCH study

BACKGROUND COPD affects over 5% of the adult population, and it is the only major cause of mortality that is increasing worldwide. Patients with COPD don’t die usually of respiratory failure: indeed lung cancer and cardiovascular diseases are the leading causes of mortality in patients with mild to moderate COPD. Pulmonary and systemic inflammations are prominent. Inhaled corticosteroids have little effect on the rate of decline of lung function, but they reduce the frequency of exacerbations, especially when combined with an inhaled long-acting beta-agonist. AIM OF THE STUDY The combination of the long-acting beta-agonist salmeterol (SM) and the inhaled corticosteroid fluticasone propionate (FP) would reduce mortality among patients with COPD, as compared with usual care. The primary end-point was the time to death from any cause by 3 years. Secondary end-points were the frequency of exacerbations and health status. PATIENTS AND METHODS Of 8,554 patients recruited, 6,184 underwent randomization; the mean age was 65 years, and the mean value of postbronchodilator FEV1 was 44% of the predicted value. This double-blind study was conducted in 444 centers of 42 countries. After a 2-week run-in period, eligible patients were randomly assigned to treatment with the combination of SM at a dose of 50 μg and FP at a dose of 500 μg or SM alone at a dose of 50 μg, FP alone at a dose of 500 μg, or placebo, all taken as a dry powder with the use of an inhaler bid for 3 years. RESULTS There were 875 deaths within 3 years after randomization. The proportions of deaths from any cause at 3 years were 12.6% in the combination therapy group, 15.2% in the placebo group, 13.5% in the SM group, and 16.0% in the FP group. The absolute risk reduction for death in the combination-therapy group as compared with the placebo group was 2.6%, and the hazard ratio was 0.825 (95% confidence interval [CI], 0.681 to 1.002; p = 0.052), corresponding to a reduction in the risk of death at any time in the 3 years of 17.5% (95% CI, –0.2 to 31.9). DISCUSSION In this trial, the reduction in mortality from any cause did not meet the level of statistical significance (p = 0.052), but the treatment with the combination regimen resulted in significantly fewer exacerbations and improved health status and lung function, as compared with placebo. Mortality could be influenced mainly by factors unresponsive to the study drugs, or it is possible that this study was underpowered to detect this effect. There was also a high withdrawal rate, which was highest among patients in the placebo group. CONCLUSIONS Even though p = 0.052 is not statistically significant, 126 deaths for every 1,000 treated in the combination-therapy group, after 3 years, instead of 152 in the placebo group, is anyway an important result? Further investigation is needed in future large, prospective trials.

Comparable effect of a leukotriene receptor antagonist and long-acting beta2-adrenergic agonist in cough variant asthma

Cough variant asthma (CVA) is a common cause of chronic persistent cough, in which allergic airway inflammation may play a role. Although current guidelines recommend bronchodilators and anti-inflammatory drugs for the treatment, comparison of the efficacy of these medications has not been investigated. This study was designed to evaluate the effectiveness of pranlukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta₂-adrenergic agonist, in the treatment of CVA. The study was a randomized, controlled, parallel-group, multicenter trial. After a 4-week run-in period, 49 patients with newly diagnosed CVA were assigned to receive oral pranlukast (225 mg, b.i.d.) or inhaled salmeterol (100 μg, b.i.d.) for 4 weeks. Primary outcome measure was cough symptom and secondary outcome measures were pulmonary function and eosinophilic airway inflammation. Treatment with pranlukast and salmeterol each decreased cough symptom scores, where the changes from baseline values were significantly greater in the pranlukast group than in the salmeterol group. Forced expiratory volume in 1 second and peak expiratory flow (PEF) increased in the two treatment groups with the same magnitudes, but significant decreases in diurnal variation of PEF and eosinophil counts and eosinophil cationic protein contents in the peripheral blood and induced sputum were observed only in the pranlukast group. In view of antitussive and anti-inflammatory actions, the leukotriene receptor antagonist pranlukast seems to be more effective than the long-acting beta₂-adrenergic agonist salmeterol in the treatment of CVA.

Cost-effectiveness of combination fluticasone propionate&amp;ndash;salmeterol 250/50 &amp;mu;g versus salmeterol in severe COPD patients

To estimate the cost-effectiveness of fluticasone propionate-salmeterol combination (FSC) compared to salmeterol for maintenance therapy in severe chronic obstructive pulmonary disease (COPD). Pooled economic analysis. We performed an economic analysis of pooled data from two randomized clinical trials (combined N = 1554) that evaluated the effect of maintenance therapy with FSC (250/50 microg twice daily) or salmeterol (50 microg twice daily) on exacerbation rates in patients with severe COPD. We calculated exacerbation rates and applied standardized costs to exacerbation-related health care utilization reported in the trials (office, urgent care, and emergency department visits; hospitalizations; and oral corticosteroids and antibiotics) to determine cost differences between FSC and salmeterol treatment outcomes. Annual rates of any exacerbation and moderate/severe exacerbation were lower in the FSC group than the salmeterol group (4.91 vs 5.78 and 1.32 vs 2.00 respectively, both P < 0.05). Total adjusted annual COPD related exacerbation and therapeutic costs were $4,842 (95% CI; $4,731-$4,952) in the FSC group and $5,066 (95% CI; $4,937-$5,195) in the salmeterol group. FSC combination therapy is associated with reduced risk of any exacerbation and moderate/severe exacerbation, and incurs lower annual COPD-related health care costs compared to treatment with salmeterol. This analysis demonstrates that FSC therapy may be advantageous from both a clinical and cost-benefit standpoint for patients with severe COPD.

Salmeterol use and risk of hospitalization among emergency department patients with acute asthma

The safety of inhaled long-acting beta2-agonists (LABAs) in the treatment of chronic asthma remains controversial and has not been evaluated in emergency department (ED) patients with acute asthma. To determine whether ED patients undergoing long-term LABA therapy would have increased risk of asthma-related hospitalization compared with those not undergoing LABA therapy and whether concurrent long-term inhaled corticosteroid (ICS) therapy would mitigate this risk. Prospective cohort study of patients aged 12 to 54 years with acute asthma in 115 EDs. Four patient groups were created based on their asthma regimen: no ICS or salmeterol (group A), salmeterol monotherapy (group B), ICS monotherapy (group C), and combination ICS and salmeterol (group D). Of the 2,236 included patients, group A had 1,221 patients (55%), group B had 48 patients (2%), group C had 787 patients (35%), and group D had 180 patients (8%); 489 patients (22%) required hospitalization. In a multivariable model controlling for 20 factors and using group A as the reference, group B had an increased risk of hospitalization (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.0-4.9), whereas groups C (OR, 1.1; 95% CI, 0.8-1.5) and D (OR, 1.2; 95% CI, 0.8-1.9) did not. Among ED patients with acute asthma, those undergoing salmeterol monotherapy had an increased risk of hospitalization; however, this risk was not seen among patients undergoing combination ICS-salmeterol therapy. Our findings provide data from a unique ED population on clinical response to acute asthma treatment among patients undergoing long-term LABA therapy.

Evaluating the cost-effectiveness of tiotropium versus salmeterol in the treatment of chronic obstructive pulmonary disease

To assess the cost-effectiveness of 3 treatments (tiotropium, salmeterol, and no treatment) in patients with moderate chronic obstructive pulmonary disease (COPD). A Markov model with a time horizon of 1 year was developed. A hypothetical cohort of 100,000 subjects with moderate COPD with mean age of 65 years, smoking history of 50 pack-years, and disease duration of 9.5 years were included in the model. The efficacy and withdrawal data were taken from published randomized clinical trials. The effectiveness measure was exacerbations avoided per patient per year. Incremental cost-effectiveness ratio (ICER) was calculated as additional cost per patient to prevent 1 exacerbation, compared with the next most expensive option. A payer's perspective was used and only direct costs were included in the study. Sensitivity analyses were conducted to test the robustness of the baseline estimates and study assumptions. The mean annual costs for the no treatment, salmeterol, and tiotropium groups were $392.1, $1268.7, and $1408.6, respectively. The ICER of tiotropium compared with no treatment was $1817.36 per exacerbation avoided, while the ICER of salmeterol compared with no treatment was $2454.48 per exacerbation avoided. Thus, in patients with moderate COPD, tiotropium is more cost-effective than salmeterol and no treatment.

A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD.

The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3%) compared to the tiotropium group (6%). Fatal CV events occurred in 1% of the salmeterol plus fluticasone group compared to 3% in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95% of patient outcome accounted for, tiotropium was associated with a significant 13% reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75% of patient outcome accounted for, tiotropium was associated with a non-significant 11% reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium.

Faster onset of action of formoterol versus salmeterol in patients with chronic obstructive pulmonary disease: A multicenter, randomized study

Background Chronic obstructive pulmonary disease (COPD) is a growing public health problem that has increased in recent years. It similarly affects men and women, especially those who smoke. The goals of COPD pharmacotherapy are to improve lung function, reduce symptoms, prevent exacerbations, and improve patients' health status. Bronchodilators are the foundation of treatment for COPD, and the long-acting β 2-agonists formoterol and salmeterol are both indicated for regular use by patients with stable COPD. Objective A clinical study was conducted to compare the onset of bronchodilator effects following treatment with formoterol 12 μg administered twice-daily (BID) or salmeterol 50 μg BID. The trial also assessed whether the bronchodilator effects of treatment resulted in significant differences in clinical response. Methods This was a randomized, multicenter, open-label, parallel-group study of formoterol 12 μg BID versus salmeterol 50 μg BID, both administered for 28 days. Patients were current or previous smokers aged ≥40 years, with a diagnosis of stable COPD. The primary efficacy variable was change from baseline in forced expiratory volume in 1 s (FEV 1) 5 min after drug administration on day 28. Secondary efficacy variables included changes from baseline in the 6-min walk test (6MWT) and rescue medication use. The primary variable was assessed by analysis of covariance, with baseline FEV 1 as the covariate. Results A total of 270 patients were randomized to formoterol 12 μg BID ( n = 137) or salmeterol 50 μg BID ( n = 133). In the intent-to-treat population the least square (LS) mean change from baseline in FEV 1 at 5 min postdose on day 28 was 0.13 L in the formoterol group compared with 0.07 L in the salmeterol group ( P = 0.022). At 30 min postdose on day 28, the LS mean change from baseline in FEV 1 was 0.17 L in the formoterol group compared with 0.07 L in the salmeterol group ( P < 0.001). Similar changes were reported at 60 min postdose (0.19 L for the formoterol group versus 0.13 L for the salmeterol group, P = 0.069). Patients in the formoterol group walked longer distances in the 6MWT and used less rescue medication compared with patients in the salmeterol group, although the differences were not statistically significant. Conclusions Significantly greater improvements from baseline in FEV 1 were observed at 5 and 30 min postdose with formoterol 12 μg compared with salmeterol 50 μg after 28 days of treatment. Numeric improvements in the 6MWT and rescue medication use were also observed with formoterol.

The Salmeterol Multicenter Asthma Research Trial: A Comparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy Plus Salmeterol

Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. Chest. 2006;129:15–26 PURPOSE OF THE STUDY. To compare the safety of salmeterol or placebo added to usual asthma care. STUDY POPULATION. Subjects who were &amp;gt;12 years old with asthma (as judged by the study physician) and were currently receiving a prescription asthma medication. METHODS. This was a multicenter, randomized, double-blind, parallel group, placebo-controlled observational surveillance study conducted at 6163 US sites with 1316 investigators between 1996 and 1999 (phase 1) and 2000 and 2003 (phase 2). The primary purpose was to compare respiratory and asthma-related outcomes in subjects who were receiving usual asthma pharmacotherapy plus placebo or usual care plus salmeterol. Subjects were recruited by large-scale advertisement and assigned geographically to the closest site (phase 1) and directly by study investigators (phase 2). A single clinic visit was performed to determine eligibility, obtain consent and baseline data, and dispense a 28-week supply of study medications and instructions. Subjects were told to continue their baseline asthma medications, and those without a short-acting β agonist were given albuterol. Telephone follow-up was obtained every 4 weeks. Adherence was not measured or reinforced. RESULTS. Almost 25% of the subjects dropped out of the study before 28 weeks. At baseline, nearly all of the subjects were taking short-acting β agonists, but only 47% were taking inhaled corticosteroids (ICSs) (49% of white subjects and 38% of black subjects). The study was terminated in 2003 because of safety concerns and difficulty with recruitment (of planned 60 000 subjects). There were 50 combined respiratory-related deaths or life-threatening experiences in the salmeterol group versus 36 in the placebo group (relative risk [RR]: 1.4; 95% confidence interval [CI]: 0.91–2.14). There were 24 respiratory-related deaths in the salmeterol group and 11 in the placebo group (RR: 2.16; 95% CI: 1.06–4.41). There were 13 asthma-related deaths in the salmeterol group (6 white and 7 black) and 3 in the placebo group (RR: 4.37; 95% CI: 1.25–15.34). The increased risk was primarily in black subjects with combined asthma-related deaths or life-threatening experiences of 19 in the salmeterol group versus 4 in the placebo group (RR: 4.92; 95% CI: 1.68–14.45). Half of the black subjects and 71% of the white subjects who had asthma-related deaths were not on ICS at baseline, but the impact of ICS on prevention of asthma or respiratory death or life-threatening experiences could not be analyzed because of the study design. The death rate for subjects exposed to salmeterol in the Salmeterol Multicenter Asthma Research Trial was 1.98 per 1000 person-years. CONCLUSIONS. The authors concluded that there were small but statistically significant increases in respiratory- and asthma-related deaths and combined asthma-related deaths or life-threatening experiences in the total population in the salmeterol group compared with placebo. The risk was greater in the black subjects. REVIEWER COMMENTS. This study was difficult to interpret, because the differentiation between respiratory-related versus asthma-related deaths was not clearly defined. The reasoning behind separating the analysis by study phase is also unclear. Health care providers should discuss the Food and Drug Administration's long-acting β-agonist black-box warning (see www.fda.gov/cder/drug/infopage/LABA/default.htm) with patients and caregivers before and while on therapy. Primary care providers should consider specialty evaluation before starting long-acting β agonists to ascertain necessity. Additional studies are ongoing to assess the safety of combined products such as fluticasone/salmeterol and mometasone/formoterol. Long-acting β agonists should not be used as first-line therapy for asthma treatment and should only be used in combination with ICSs.

Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease

Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease (COPD), but their effect on survival is unknown. We conducted a randomized, double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily (combination regimen), administered with a single inhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination regimen and placebo; the frequency of exacerbations, health status, and spirometric values were also assessed. Of 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P=0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P<0.001 for comparisons between these treatments and placebo). The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients. (ClinicalTrials.gov number, NCT00268216 [ClinicalTrials.gov].).