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Norris SL, Yen PY, Dana TL, et al. Drug Class Review: Beta2-Agonists: Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2006 Nov.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Drug Class Review: Beta2-Agonists: Final Report [Internet].

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Results

Database searches identified 6,629 citations. Following application of inclusion/exclusion criteria, 104 studies were included in this review (Figure 1). Included studies for each between-drug comparison are depicted in Table 3. We identified one or more studies for all comparisons of interest except for levalbuterol: available studies only compared it to albuterol and not to any other drugs. The quality assessment of nine studies was rated as poor for measures of effectiveness.12–21

Figure 1

Figure 1

Literature search results

Table 3. Beta2-agonist comparison table.

Table 3

Beta2-agonist comparison table.

Systematic reviews

No systematic reviews were identified which provided head-to-head data on the comparisons of interest to this review. In the Cochrane Database of Systematic Reviews, there are a number of reviews related to inhaled beta2-agonists. None of these reviews fulfilled our inclusion criteria; the most common reason was their focus on placebo-controlled trials only (and not head-to-head trials). Since these reviews provide additional background and useful information, we have briefly summarized their scope and conclusions in Appendix C.

Efficacy and effectiveness

Key Question 1. When used in adults with asthma or chronic obstructive pulmonary disease (COPD), are there differences in efficacy or effectiveness among long-acting, inhaled beta2-agonists, when used in the outpatient setting?

Key Question 2. When used in adults with asthma or COPD, are there differences in efficacy or effectiveness among the following short-acting inhaled beta2-agonists when used in the outpatient setting: albuterol, fenoterol, levalbuterol, pirbuterol, metaproterenol and terbutaline?

Key Question 3. When used in children with asthma, are there differences in efficacy or effectiveness among long-acting, inhaled beta2-agonists, when used in the outpatient setting?

Key Question 4. When used in children with asthma, are there differences in efficacy or effectiveness among the following short-acting inhaled beta2-agonists when used in the outpatient setting: albuterol, fenoterol, levalbuterol, pirbuterol, metaproterenol and terbutaline?

Salmeterol vs formoterol

Demographic and study characteristics are summarized in Table 4 and effectiveness outcomes in Table 5.

Table 4. Salmeterol vs Formoterol: Demographic and Study Characteristics of Included Studies.

Table 4

Salmeterol vs Formoterol: Demographic and Study Characteristics of Included Studies.

Table 5. Salmeterol vs Formoterol: Effectiveness Outcomes of Included Studies.

Table 5

Salmeterol vs Formoterol: Effectiveness Outcomes of Included Studies.

Adults with asthma

Studies with either effectiveness or safety data encompassed a total of 1676 participants in 10 studies; mean age 49.5 years and half of the study participants were female (Table 4 and Evidence Table 3). Note that various formulations are presented, but only 'Foradil® Aerolizer® (formoterol) and Serevent Discus® (salmeterol) are available in the U.S.

Data were not frequently provided on effectiveness outcomes. Of the four fair-quality studies with effectivness data,35, 41, 116, 117 three of these compared dry power delivery systems (formoterol Tubohaler® or Aerolizer® with salmeterol Accuhaler® or Serevent Diskhaler®). The fourth study compared formoterol and salmeterol delivered via MDI (neither of which are currently available in the U.S.).41

No differences were found between formoterol and salmeterol (both delivered via dry powder systems) for the outcomes of symptoms (three studies22, 23, 35, 44), use of rescue medications (three studies 22, 23, 35, 44), healthcare utilization (two studies22, 23, 44), and quality of life (one study39) in the fair-quality studies examining these outcomes. Campbell and colleagues22 noted more symptom-free days and reduced severity of daytime asthma symptoms at 4 weeks with formoterol Turbohaler compared to salmeterol Accuhaler, but these differences were not sustained at 8-week follow-up.

Formoterol via Turbohaler was prefered over salmeterol MDI (the latter is no longer available in the U.S.); there was no difference in patient preference between formoterol via Turbohaler and salmeterol via Accuhaler.22 Formoterol via MDI was preferred by more patients than salmeterol via MDI in a second study.41 Both of these studies were sponsored by the makers of formoterol.

Children with asthma

One open-label trial presented effectiveness data31, 32 among three studies which addressed this population using dry powder delivery systems. Children aged 6 to 17 years (n=156) used formoterol 9ug (a dosage not currently available in the U.S.) or salmeterol 50ug bid, added to current inhaled steroid use. More patients using formoterol discontinued the study after randomization (21 with formoterol [5 due to deterioration in asthma, 4 due to AEs]; 12 with salmeterol [4 due to deterioration in asthma, 1 due to AEs]). Compliance was similar in the two groups. Both drugs decreased the as-needed use of SABAs, with a greater decline with formoterol by week 12 (inhalations/24h; p=0.043). Multiple other comparisons were made: there was no significant difference between groups for frequency of poorly controlled days (p=0.107), frequency of mild exacerbations (p=0.051), percentage of patients experiencing a severe exacerbation by week 12 (p>0.05), and school attendance. Formoterol was favored for clinician-assessed asthma severity score at night (p=0.049) and patient-assessed asthma severity score during the daytime (p=0.052).31, 32

Adults or children with EIA

Only one study was identified which examined EIA. Richter and colleagues38 examined acute protection against exercise-induced bronchoconstriction in 25 adults. Exercise challenges were performed on 12 separate days and up to 60 minutes after inhalation of a single dose of one of formoterol (12 ug Turbohaler), salmeterol (50 ug Diskus) and terbutaline (500 ug Turbohaler) or placebo. Maximum fall in FEV1 did not differ significantly among the treatments. The onset of bronchodilation, however, was slower after salmeterol compared to both other treatments (p<0.05). Bronchodilation, expressed as % increase of FEV1 compared to baseline, was evaluated between inhalation of study drug and start of exercise. Formoterol provided greater bronchodilation than salmeterol at 5 (p<0.01), 30 (p<0.05), and 60 minutes (p<0.01) after inhalation.

COPD

Seven small studies examined these drugs among persons with COPD, with a total of 145 participants.24–29, 34 The mean age was 62.2 years and the majority of subjects were male. Two studies that examined symptoms found no difference between the two drugs. Kottakis and colleagues34 found no significant difference between formoterol 12ug (dry powder via Aerolizer ®) and salmeterol 50ug (via Aerolizer®) at 1 and 4-hour follow-up for breathing effort and breathing discomfort. In a single-dose study29 there were no differences in dyspnea symptoms 30 minutes after treatment with salmeterol 50ug or formoterol 12 ug, both via MDI. There were no other head-to-head data available on effectiveness outcomes among persons with COPD.

Albuterol vs levalbuterol

Demographic and study characteristics are summarized in Table 6 and effectiveness outcomes in Table 7.

Table 6. Albuterol vs Levalbuterol: Demographic and Study Characteristics of Included Studies.

Table 6

Albuterol vs Levalbuterol: Demographic and Study Characteristics of Included Studies.

Table 7. Albuterol vs Levalbuterol: Effectiveness Outcomes of Included Studies.

Table 7

Albuterol vs Levalbuterol: Effectiveness Outcomes of Included Studies.

Adult asthma

Nelson and colleagues76 and Pleskow et al.78 examined 362 patients 12 years of age and older with moderate to severe asthma. Each participant was given a nebulizer three times daily of either levalbuterol (0.63 or 1.25 mg), racemic albuterol (1.25 mg or 2.5 mg), or placebo for 4 weeks. The mean number of puffs of rescue medication used per day decreased in all treatment groups and the within-group change was significant for levalbuterol 1.25 mg (p<0.001) and of borderline significance for racemic albuterol 2.5 mg (p=0.056). Rescue medication use increased in the placebo group (p=0.019). The percentage of patients reporting `asthma' or `asthma increase' (these were not defined) appeared similar among all groups (statistics not provided). Other effectiveness measures were not reported in this study.

A controlled clinical trial77 (n=91) examined adults presenting to the emergency department with asthma. Treatment consisted of three doses of albuterol (2.5 and 5.0 mg) or levalbuterol (0.63 to 5.0 mg) delivered via nebulizer over 60 minutes. The primary outcomes of this study were pulmonary function measures and the study was not powered to examine healthcare utilization. In the discussion section of the paper, however, the authors indicate that patients treated with levalbuterol required less additional therapy and a greater percentage were discharged after three doses than after treatment with albuterol. However, hospitalization rates were similar between the two drugs for matched dosages. (Rates for levalbuterol were: 0.63 mg, 0%; 1.25 mg, 7%; 2.5 mg, 8%; 3.75 mg, 29%; and 5.0 mg, 8%. Rates for albuterol were: 2.5 mg, 7%; 5.0mg, 0%). No statistical comparisons were presented for these outcomes.

An HFA metered-dose inhaler containing levalbuterol (Xopenex HFA®) was approved in December 2005 for the treatment or prevention of bronchospasm in adults, adolescents, and children 4 years of age and older with reversible obstructive airway disease. We did not identify any published data on the comparative effectiveness or safety of this preparation with respect to albuterol.

Pediatric asthma

Symptoms and rescue medication use were not different between drugs in the four pediatric studies that compared albuterol and levalbuterol.73, 75, 79, 81 Two of these studies took place in the ER. Qureshi and colleagues79 examined children aged 2 to 14 years (n=129) presenting to a pediatric emergency department with a moderate to severe acute asthma exacerbation (asthma score >8 out of a possible score of 15). These children were given three nebulized treatments of either albuterol 2.5 to 5.0 mg (depending on weight) or levalbuterol 1.25 to 2.5 mg at 20-minute intervals, with subsequent treatments given at 30- and 60-minute intervals based on clinical assessment and pulmonary function testing. There were no significant differences between groups after the first, third, and fifth nebulizer treatment for the primary outcome of improvement in asthma score (validated score based on respiratory rate, auscultation, retractions, dyspnea, and oxygen requirement) or percentage of predicted FEV1

Hardasmalani and colleagues73 (n=70) randomized patients aged 5 to 21 presenting to the emergency department to levalbuterol 1.25 mg or albuterol 2.5 mg via nebulization, along with ipratropium bromide 250 ug in children <30 kg and 500 ug in children >30 kg. Three treatments were given as needed at 20-minute intervals, along with oral steroids after the second treatment. There were no differences among groups for oxygen saturation, respiratory rate, peak flow rates, and the need for extra treatments.

Two studies examined regular daily use of levalbuterol and albuterol. Milgrom and collegues75 examined 338 children aged 4 to 11 years with at least mild asthma for 60 days prior to screening and randomized them to receive 21 days of three-times-a-day of either levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg, or placebo via nebulizer in a double-blind fashion. No significant differences were noted among the treatment groups for overall asthma symptom score, symptom-free days, quality of life, or rescue medication use. Asthma control days were not difference among groups for the first 14 days of treatment, however, from day 14 to 21, levalbuterol 0.31 mg was associated with significantly greater improvement in asthma control days than levalbuterol 0.63 mg and albuterol 1.25 mg (p<0.04 for both comparisons).

Skoner and colleagues81 randomized asthmatic children age 2 to 5 years to albuterol (1.25 mg or 2.5 mg, depending on weight) or levalbuterol (0.31 mg or 0.63 mg, independent of weight), each given three times a day over 21 days via nebulizer. Symptom score improved in all groups over the 3 weeks, with no significant difference among groups. There were also no differences among groups for use of rescue medications, the number of uncontrolled asthma days, functional status score, or Child Health Status Questionnaire responses. The Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ) improved more for the levalbuterol groups, although between-group differences were not significant. In a subgroup analysis of patients less than 33 pounds, overall PACQLQ score was significantly improved after levalabuteral 0.63 mg than albuterol (p=0.016). This study was of fair quality: although it reported using intention-to-treat analyses for efficacy/effectiveness measures, the number of subjects actually analyzed was unclear. Study completion rate was 83.4%.

Healthcare utilization outcomes varied among the three studies that examined these outcomes.68, 73, 79 These all took place in the emergency department, and were similarly-designed RCTs, with blinding of the patient and treating physician.

Qureshi and colleagues79 (see details above) reported a per-protocol analysis of 129, primarily African-American, children. Ten patients were excluded from analysis, including six due to protocol violation. The authors noted no differences in the secondary outcomes of percent of patients hospitalized from the emergency department, length of care in the ER, median number of nebulizations, or rate of adverse events. In the levalbuterol group 11% of patients were hospitalized; in the albuterol group the rate was 13%. The baseline rate of hospitalization was 13%; the authors indicate their study was underpowered to detect a possible difference in rates between groups.

Similar results were reported by Hardasmalani and colleagues,73 who also examined hospital admission rates as a secondary outcome after treatment of children and adolescents in the emergency department. In the albuterol group, 2 of 34 patients (2.9%) were admitted compared to 3 of 36 children (4.3%) in the levalbuterol group (between-group, p=0.528).

In contrast to the two studies just discussed, a significant decrease in hospital admission rate was noted with the use of levalbuterol in the emergency department in a study by Carl and associates.68 This study (n=547) of predominantly African-American males with moderate to severe chronic asthma, randomized children aged 1 to 18 years upon presentation to the emergency room, to three treatments via nebulizer at 20-minute intervals of either 1.25 mg levalbuterol or 2.5 mg of albuterol. The average hospital admission rate for the last 5 years was 42% for this study setting, and this study was powered to examine hospital admission rates as a primary outcome.

Carl and colleagues68 noted a hospital admission rate of 122/269 (45%) with albuterol and 101/278 (36%) after levalbuterol (between-group, p=0.02). The use of albuterol in the 24 hours prior to the emergency department visit correlated with hospital admission rate (p=0.002). After controlling for recent use of albuterol (>3 aerosols in the last 24 hours), levalbuterol was still associated with a lower admission rate 43% vs 53% with albuterol (RR, 1.25, 95% CI, 1.01–1.51). Length of stay (p=0.25), mean number of aerosols in the emergency department (p=0.08), and hospital length of stay for those admitted (p=0.63), did not differ between groups.

Exercise-induced Asthma

There were no studies comparing albuterol and levalbuterol in persons with EIA.

COPD

The single study comparing these two drugs70 did not provide data on effectiveness outcomes.

Albuterol vs metaproterenol

Demographic and study characteristics are summarized in Table 8. There were no effectiveness data for any of these five fair-quality studies.82–84, 86, 87

Table 8. Albuterol versus Metaproterenol: Demographic and Study Characteristics of Included Studies.

Table 8

Albuterol versus Metaproterenol: Demographic and Study Characteristics of Included Studies.

In an exercise-challenge study of adolescents with exercise-induced bronchospasm,83 albuterol and metaproterenol were equally efficacious in blocking exercise-induced bronchospasm initially. The duration of action of albuterol was significantly longer than for metaproterenol (p<0.05).

Albuterol vs pirbuterol

Demographic and study characteristics are summarized in Table 9.

Table 9. Albuterol vs Pirbuterol: Demographic and Study Characteristics of Included Studies.

Table 9

Albuterol vs Pirbuterol: Demographic and Study Characteristics of Included Studies.

Of the three studies (in four publications) which provided direct comparative data on these drugs,13, 14, 87, 88 two were of poor quality,13, 14 and one was of fair quality.87 None of these studies provided data on effectiveness outcomes.

Metaproterenol vs pirbuterol

Demographic and study characteristics are summarized in Table 10.

Table 10. Metaproterenol versus Pirbuterol: Demographic and Study Characteristics of Included Studies.

Table 10

Metaproterenol versus Pirbuterol: Demographic and Study Characteristics of Included Studies.

There were no data on effectiveness outcomes in two identified studies of COPD87, 112 and in one study of asthma in adults.113

Albuterol vs fenoterol

Demographic and study characteristics are summarized in Table 11 and effectiveness outcomes in Table 12.

Table 11. Albuterol vs Fenoterol: Demographic and Study Characteristics of Included Studies.

Table 11

Albuterol vs Fenoterol: Demographic and Study Characteristics of Included Studies.

Table 12. Albuterol vs Fenoterol: Effectiveness Outcomes of Included Studies.

Table 12

Albuterol vs Fenoterol: Effectiveness Outcomes of Included Studies.

Only one of the 24 head-to-head studies identified comparing these two drugs reported outcomes other than efficacy data. Manicatide and colleagues56 reported drug preference (all delivered by pressurized aerosol) by patients with COPD, with 30% of subjects preferring salbutamol, 25% terbutaline, 33% preferred fenoterol, and 11% were undecided. There was no clarification as to how patient preference was measured. No between-group statistics were provided and no health or utilization outcomes were reported.

Albuterol vs terbulatine

Demographic and study characteristics are summarized in Table 13 and effectiveness outcomes in Table 14.

Table 13. Albuterol vs Terbutaline: Demographic and Study Characteristics of Included Studies.

Table 13

Albuterol vs Terbutaline: Demographic and Study Characteristics of Included Studies.

Table 14. Albuterol vs Terbutaline: Effectiveness Outcomes of Included Studies.

Table 14

Albuterol vs Terbutaline: Effectiveness Outcomes of Included Studies.

The use of rescue medications was similar in two studies that examined this outcome.18, 21 Lindsay and colleagues21 examined 46 subjects over the age of 7 years, and the mean number of doses of beta2-agonists taken over 24 hours was 3.2 (SD 1.6) for terbutaline 1.6 mg and 5.8 (SD 2.3) for salbutamol 0.58 ug (no between-group comparisons). In an adult asthma population, Gioulekas et al.18 did not find a significant difference in rescue medication usage.

Symptom scores were not different between albuterol and terbutaline in adults with asthma in two studies.18, 21 The mean daytime asthma symptom score (p<0.001) and the mean nighttime score (p<0.05) were lower with terbutaline 0.5 mg twice daily compared to albuterol 0.1 mg two puffs twice daily, in a third RCT of 159 adults with asthma.100 No rescue medications were used during this study.

In pediatric asthma, there was no significant difference between the two drugs for symptoms90, 97, 99 and respiratory rate decreased after both treatments.97

Among persons with COPD, only one head-to-head study compared these two drugs and reported outcomes other than efficacy data. Manicatide and colleagues56 reported patient preference, with 30% of subjects preferring salbutamol, 25% terbutaline, 33% preferred fenoterol, and 11% were undecided. No between-group statistics were provided and no health or utilization outcomes were reported.

In EIA in a pediatric population, the only effectiveness outcome reported was the need for aminophylline treatment, with 21% of patients receiving albuterol 0.2 mg needing treatment and 8% of those treated with terbutaline 0.25 mg requiring aminophylline98 (no between-group statistics).

Metaproterenol vs fenoterol

Demographic and study characteristics are summarized in Table 15. No effectiveness outcomes were reported.

Table 15. Metaproterenol versus Fenoterol: Demographic and Study Characteristics of Included Studies.

Table 15

Metaproterenol versus Fenoterol: Demographic and Study Characteristics of Included Studies.

Metaproterenol vs terbutaline

Demographic and study characteristics are summarized in Table 16. No effectiveness outcomes were reported.

Table 16. Metaproterenol versus Terbutaline: Demographic and Study Characteristics of Included Studies.

Table 16

Metaproterenol versus Terbutaline: Demographic and Study Characteristics of Included Studies.

Fenoterol vs terbutaline

Demographic and study characteristics are summarized in Table 17. Effectiveness outcomes are summarized in Table 18.

Table 17. Fenoterol vs Terbutaline: Demographic and Study Characteristics of Included Studies.

Table 17

Fenoterol vs Terbutaline: Demographic and Study Characteristics of Included Studies.

Table 18. Fenoterol vs Terbutaline: Effectiveness Outcomes of Included Studies.

Table 18

Fenoterol vs Terbutaline: Effectiveness Outcomes of Included Studies.

Among adults with asthma, Anderson and colleagues104 found no significant difference in symptom scores between fenoterol 0.4 mg and terbutaline 0.5 mg. There was no difference in patient preference between the two drugs in another study.111

Only one study examined patients with COPD and found that 33% of participants preferred fenoterol and 25% terbutaline.56

Pirbuterol vs terbutaline

Demographic and study characteristics are summarized in Table 19. No effectiveness outcomes were reported.

Table 19. Pirbuterol vs Terbutaline: Demographic and Study Characteristics of Included Studies.

Table 19

Pirbuterol vs Terbutaline: Demographic and Study Characteristics of Included Studies.

Safety

Key Question 5. When used in adults with asthma or COPD, are there differences in safety or rates of adverse events among long-acting, inhaled beta2-agonists, when used in the outpatient setting?

Key Question 6. When used in adults with asthma or COPD, are there differences in safety or rates of adverse events among the following short-acting inhaled beta2-agonists when used in the outpatient setting: albuterol, fenoterol, levalbuterol, pirbuterol, metaproterenol and terbutaline?

Key Question 7. When used in children with asthma, are there differences in safety or rates of adverse events among long-acting, inhaled beta2-agonists, when used in the outpatient setting?

Key Question 8. When used in children with asthma, are there differences in safety or rates of adverse events among the following short-acting inhaled beta2-agonists, when used in the outpatient setting: albuterol, fenoterol, levalbuterol, pirbuterol, metaproterenol and terbutaline?

Overview of adverse events

Withdrawal rates are presented in Table 20 and specific adverse events for each drug comparison are shown in Appendix E. Adverse events primarily related to sympathomimetic side effects are expected with these medications and are discussed below. There were also a broad range of gastrointestinal, musculoskeletal, and other miscellaneous adverse events which are noted in Appendix E. There were no apparent differences between the various drugs being compared in this review.

Table 20. Withdrawals from Included Studies*.

Table 20

Withdrawals from Included Studies*.

Salmeterol vs formoterol

Adults

Rates of total withdrawals and withdrawals due to adverse events from studies were similar between these two drugs and rates of total withdrawals ranged from 0 to 12.5% (Table 20).

There were no data on the comparative effect of these two drugs on blood pressure. Neither salmeterol (single dose 50 ug) or formoterol (single dose 24 ug) had significantly different effects on maximum heart rate response to salbutamol 1 to 2 hours after treatment in a fair-quality study24 and a poor-quality study.19 Cazzola and colleagues25 reported a "statistically significant" increase in heart rate with a single dose of formoterol 24ug (not available in the U.S.) compared to formoterol 12ug and salmeterol 50 ug between 2 and 9 hours post inhalation (p<0.05) in COPD patients with preexisting cardiac arrhythmias. There was no significant difference in the increase in heart rate between single-dose formoterol 12 ug and salmeterol 50 ug (p<0.05).

One participant noted palpitations with formoterol 12ug,28 and in a COPD population 4 of 241 patients noted palpitations with formoterol 12 ug twice daily over 6 months; no palpitations were noted in the salmeterol group.44 In a 12-hour study, 5 of 28 patients noted some subjective symptoms (either tachycardia, palpitation, or tremor) with formoterol 24ug and no patient noted adverse events after salmeterol.36 Cazzola and colleagues25 reported similar numbers (p>0.05) of ventricular premature beats over 24 hours after formoterol (12ug ) and salmeterol (50ug).

Potassium decreased over a 9-hour follow-up period with a maximum decrease of 1.12 mmol/L after formoterol 24ug, 0.45 mmol/L after salmeterol 50 ug and 0.49 mmol/L after formoterol 12ug.25 There were no significant changes in potassium 1 hour after treatment in a poor-quality study examining this outcome.19 There were no data on the comparative effect of these drugs on blood glucose.

The reporting of headache ranged from 0 to 5% of study participants, with no differences reported between study drugs.16, 28, 32, 37, 44 Tremor was reported in a small percent of participants taking both formoterol or salbutamol, with no apparent difference between the two drugs (between-group statistics not reported).19, 28, 37, 44

Children

In the single study reporting withdrawals, 26.6% of participants taking formoterol 12ug (delivered dose 9 ug, not available in the U.S.) bid and 15.8% of those taking salmeterol 50ug bid withdrew over the 12-week study.31 Withdrawals were due to deteriorating asthma control (6.3% formoterol; 5.3% salmeterol) and to adverse events (5.1% formoterol; 1.2% salmeterol). One serious adverse event was reported in each treatment group but neither was thought related to the treatment (testicular torsion and diabetes mellitus).

Palpitations were not reported in any participants in a pediatric study.37 Tremor was reported in 1 of 68 patients taking formoterol 36mg and none with lower dosages or with salmeterol 50ug.37 Headaches were reported in 22.4% of children taking salmeterol 50ug bid and 17.5% in those taking formoterol 12ug bid over 12 weeks with no significant difference between groups.31, 32

Albuterol vs levalbuterol

Adults

Total withdrawal rates ranged from 0 to 11.0% (the latter rate with levalbuterol 1.25 mg in adult asthmatic patients over 4 weeks76) among the four studies reporting these data.71, 76, 77, 118 Withdrawal rates were similar between the two drugs with neither drug consistently reporting higher rates. These studies reported several dosages for each drug and no relationship between dose and withdrawal rates was noted.

The available data indicate that heart rate increases 5 to 15 beats per minute 20 minutes after treatment with both albuterol or levalbuterol, but returns to baseline by 3 hours in adults.69, 79, 118 Between-group statistical comparisons were rarely reported; in one study of adults with asthma who were treated three times daily over 4 weeks, the increase in pulse rate 15 minutes after treatment with racemic albuterol 2.5 mg/dose was significantly greater than with levalbuterol 0.63 mg/dose (4.8 beats per minute versus 2.4; data estimated from graph) (p<0.05).76

In the only study examining blood pressure, there were no significant changes in either group.69 Palpitations118 and tachycardia76 were reported in a similar percent of patients with both drugs.

Light-headedness, dizziness, nervousness, anxiety, restlessness were reported in a number of studies with similar rates for both albuterol 1.25 to 2.5 mg and levalbuterol 0.63 to 1.25 mg.69, 76, 79 There appeared to be slightly higher rates of these symptoms with the higher dosages, but between-group statistical comparisons were not provided in most studies. Tremor was reported in three studies with comparable rates between treatment drugs.70, 76, 118

Blood glucose increased 3 hours after 4 doses of albuterol 2.5 mg and levalbuterol 1.25 mg with no significant difference between the two drugs (p=0.70).71 An increase in mean serum glucose was noted for levalbuterol 0.63 mg (2.4 mg/dL) and albuterol 2.5 mg (4.4 mg/dL) 15 minutes after treatment at day 28 of three times daily dosing.76 Maximum changes in glucose ranged from 15.9 to 62.4 mg/dL for levalbuterol and 46.4 to 57.1 mg/dL for albuterol 60 minutes after dosing in adult asthma.77

In an adult asthma population, potassium was noted to decrease 3 hours after 4 doses of albuterol 2.5 mg and levalbuterol 1.25 mg with no significant difference between the two drugs (p=0.17).71 Two other studies also recorded a decrease in potassium 1–10 hours after both levalbuterol and albuterol, with no significant difference between the two drugs.71, 77, 79

Children

Study withdrawal rates in pediatric studies were inconsistent in the two studies that reported these data. 75, 81 The overall rate of adverse events was generally similar for each treatment group: placebo 52%, levalbuterol 0.31 mg 53.4%, levalbuterol 0.63mg 60.8% and albuterol 1.25 mg 53.8%.81

Heart rate increased 5 to 15 beats per minute 20 minutes after treatment with both albuterol or levalbuterol, but returned to baseline by 3 hours.17, 75, 81 There was no significant difference between groups in the degree of increased heart rate between treatment groups.17, 68 Skoner and colleagues81 noted a greater increase in heart rate (p<0.04) with levalbuterol 0.63 mg three times daily (4.1 peats per minute) and albuterol 1.25 mg (2.6 beats per minute), both compared to levalbuterol 0.31 mg

Light-headedness, tremor and headache were reported with similar rates for up to five doses of albuterol 2.5 mg and levalbuterol 1.25 mg.79 Tremulousness was reported in 37% and 33% of pediatric patients using levalbuterol and racemic albuterol, respectively79 with no significant difference between groups.

Milgrom and colleagues75 noted a larger increase in serum glucose 60 minutes after albuterol 2.5 mg than after levalbuterol 0.63 mg on both day 0 and day 21 of treatment three times a day (p= 0.043) in children. Among children age 2 to 5 years, Skoner and colleagues81 noted an increase in serum glucose 30–60 minutes after the last dose in all groups, including the placebo group, with the greatest increase after albuterol 1.25 mg (no data presented). In a poor-quality study of children aged 3 to 11 years,17 blood glucose increased 60 minutes after treatment with levalbuterol 0.16 mg, 0.63 mg, and 1.25 mg (and not with 0.31 mg). The largest increase was 30.5 mg/dL (with 1.25 mg levalbuterol). Increases were also seen after racemic albuterol 1.25 and 2.5 mg (16 and 20 mg/dL, respectively).

A decrease in serum potassium was noted 1–10 hours after both levalbuterol and albuterol, with no significant difference between the two drugs.79 In a study of albuterol and levalbuterol given three times daily, potassium decreased more with albuterol 2.5 mg than with levalbuterol 0.63 mg and 0.31 mg (p<0.05) at day 0; there was no significant difference between the two drugs at day 21.75 Skoner and colleagues81 noted a reduction in serum potassium 30–60 minutes after the last dose in all groups, including the placebo group, with the greatest reduction after albuterol 1.25 mg (no data presented). In a poor-quality study, serum potassium levels decreased in a pediatric population 60 minutes after treatment with levalbuterol 0.63 mg (−0.5 meq/L), levalbuterol 1.25 mg (−0.5 meq/L), racemic albuterol 1.25 mg (−0.4 meq/L), and albuterol 2.5 mg (−0.5 meq/L).17

Albuterol vs metaproterenol

No data on withdrawals were provided in the included studies.

A single study86 examined the comparative effect of these drugs on blood pressure and noted that systolic blood pressure was increased in both drugs, with no significant difference between the drugs in peak pressure or area under the curve. Albuterol had shorter time to peak systolic pressure (p>0.05). Heart rate also increased with both drugs, with the peak rate greater with albuterol (p=0.05), but no significant difference in area under the curve (beats/min). There were no comparative data on cardiovascular, metabolic, or neurologic adverse events.

Albuterol vs pirbuterol

No comparative data on withdrawals or cardiovascular, metabolic, or neurologic adverse events were provided in the included studies. One comparative study in a pediatric population reported no `cardiac side effects' in 17 patients.88

Metaproterenol vs pirbuterol

Rates of withdrawals were similarly low in both treatment groups in the only available study.113

There were no comparative data on blood pressure or heart rate on these drugs. A single study in an adult population noted that `tachycardia' was reported in a 2 patients taking metaproterenol (n= 67) and 2 taking pirbuterol (n= 66).113 Headache, dizziness, tremors, nausea occurred in ≤ 6% of participants with no significant differences between treatment groups. Nervousness was reported in about 20% of patients taking pirbuterol and 10% taking metaproterenol, but this difference was also not significant (p>0.05).

Albuterol vs fenoterol

The only trial reporting withdrawals was a study of acute asthma treatment of adults in the emergency department.57 Here the only `withdrawal' was one death from asthma among 128 study participants receiving fenoterol. The other studies comparing albuterol and fenoterol were cohort48, 119 or case control60, 62 studies and rate data were not provided.

Blood pressure in adult patients decreased from 1 to 6 mm Hg for both drugs 1–2 hours following treatments. Between-group comparisons were not reported, but the both drugs appeared to have similar effects in all studies. Heart rate response was variable with a decrease of 6 beats per minute to an increase of 18 beats per minute between 15 minutes and 2 hours after treatment. Both drugs produced a change within studies, with greater increases occurring in the pediatric age groups. Palpitations were occasionally reported with both drugs,50, 66 with no difference between groups.

A minor decrease in potassium was reported in two studies,65, 66 with a greater decline with higher dosage (26 puffs of terbutaline 250 ug [decrease in potassium 0.52 mmol/l], fenoterol 200 ug [0.76 mmol/l], or albuterol 100ug [0.46 mmol/l]).66

Data were not available on the comparative effect of these drugs on blood glucose or gastrointestinal AEs. Headache was noted in a small study (n=10) with 2 patients with terbutaline 250ug, 3 patients with albuterol 100 ug, and 5 patients with fenoterol 200 ug.66

Albuterol vs terbutaline

Total withdrawals ranged from 0 to 15.6% and withdrawals due to adverse events from 0 to 6.3% in the six studies reporting these data. Rates were similar between the two study drugs. The high rate of total withdrawals occurred in an adult asthmatic population using albuterol 0.4 mg three times daily over 3 weeks; none of the withdrawals in this study were felt due to adverse events.18

Effects on systolic blood pressure (SBP) and diastolic blood pressure (DBP) were similar between the two drugs in the only study reporting these data.89 Heart rates generally increased 5 to 10 beats per minutes from 15 minutes to 2 hours after treatment, with similar changes after both drugs. Palpitations were noted in a small number of patients with both drugs.12, 66, 90, 96

Potassium decreased 0.48 meq/l after terbutaline 0.125 mg/kg and 0.85 meq/L after albuterol 0.125 mg/kg at 30 minutes post-treatment (within-group p-value <0.05 for both groups; no between-group p-values reported).93 Similar changes in potassium were noted after both terbutaline and albuterol 26 puffs each.66

Headache was reported in 20–30% of patients taking either terbutaline or albuterol in two small studies.66, 96

Metaproterenol vs fenoterol

No data on withdrawals were provided in the included studies. The sparse available data on adverse events are found in Appendix E.

Metaproterenol vs terbutaline

The single study reporting withdrawals was a 3-hour study in adult asthma and no withdrawals were noted.115

Fenoterol vs terbutaline

There were limited data on withdrawal rates, with only four studies reporting these data.106, 109, 111, 119 In a study of pediatric asthma patients, 2 of 38 participants using terbutaline withdrew due to deteriorating asthma, and none in the fenoterol group.109 In the other study of COPD sample sizes were too small to draw conclusions (1 of 2 patients taking fenoterol dropped out).119 The other studies reporting these data were also had very small sample sizes.106, 111 The sparse available data on adverse events are found in Appendix E.

Pirbuterol vs terbutaline

No data on withdrawals were provided in the included studies. The available data on adverse events are found in Appendix E.

Subpopulations

Key Question 9. Are there subgroups of patients based on demographic characteristics (age, racial groups, gender), other medications (drug-drug interactions), comorbidities (drug-disease interactions), or pregnancy for which one long-acting, inhaled beta2-agonists is more efficacious, effective, or associated with fewer adverse events than another inhaled beta2-agonist?

Key Question 10. Are there subgroups of patients based on demographic characteristics (age, racial groups, gender), other medications (drug-drug interactions), comorbidities (drug-disease interactions), or pregnancy for which one of the following short-acting, inhaled beta2-agonists is more efficacious, effective, or associated with fewer adverse events: albuterol, levalbuterol, pirbuterol, metaproterenol, terbutaline, or fenoterol?

Age and sex

No study specifically examined an older (>65 years of age) population. In several studies of COPD the mean population age was ≥ 65 years: formoterol vs salmeterol,29 albuterol vs fenoterol,67 albuterol vs levalbuterol,70 and metaproterenol vs terbutaline.87 The age range was up to 80 years in two studies comparing formoterol to salmeterol.27, 34

Consistent with the epidemiology of COPD, male participants dominated these trials and in a number of these, more than 80% of participants were male.13, 14, 26–28, 34, 63, 70, 82, 119

Several trials examined predominantly male asthmatics.49, 53, 66

No study examined a predominantly female population either as part of the main study or as a subgroup, for either asthma or COPD.

Albuterol vs levalbuterol

Datta and colleagues70 examined levalbuterol versus albuterol in a COPD population which was 83% male with a mean age of 69 years. No significant differences were noted between treatment groups for improvements in FEV1 and increase in pulse rate. There were no differences between treatment groups and in treatment groups compared to placebo group in oxygen saturation or hand tremor.

Salmeterol vs formoterol

Cazzola and colleagues27 examined the time course of salmeterol and formoterol in 16 male patients with moderate to severe COPD and mean age 64.3 years (range 50–80 years) and found no significant differences between these drugs for mean time of onset; time to mean peak response was faster with formoterol. Heart rate and blood pressure did not change significantly during the study.

In another small study of older males26 salmeterol was equally as effective, but longer acting, than formoterol. Celik and colleagues28 also noted comparable bronchodilation and side effects between the drugs in a predominantly male COPD population.

Formoterol was again noted to have faster onset of action by Kottakis and colleagues34 with a greater improvement in during the first hour, but the two drugs produced similar improvements in effort to breathe, breathing discomfort and change in effort to breathe by both 1 and 4 hours post treatment. This population of mean age 63.5 years (range 42 to 80 years) was 81% male.

Di Marco and colleagues29 compared drug effects over 120 minutes in 20 COPD patients of mean age 65 years (range not reported). Formoterol increased inspiratory capacity (% predicted) more than salmeterol. There was no significant difference between these drugs for FEV1, however. Adverse events were not reported in this study.

Albuterol vs metaproterenol

Four inhaled beta2-agonists were compared87 in 18 COPD patients of mean age 69 years (range 59–79 years): albuterol 0.18 mg, metaproterenol 1.30 mg, pirbuterol 0.4 mg, and terbutaline 0.4 mg. After single doses of the drugs, FEV1 was not different among the four agents. Patients then took the agent that provided the greatest and least response for 4-week periods; the responses to the two agents were not significantly different.

Metaproterenol was equivalent to albuterol for pulmonary function outcomes and side effects were also similar in a single small study.82

Albuterol vs pirbuterol vs metaproterenol

Peacock and colleagues87 examined these comparisons as noted above (albuterol vs metaproterenol comparison).

In a poor-quality study of 12 males,13, 14 no differences were found in lung function 4 hours after the use of pirbuterol 400 ug and salbutamol 200 ug and there were no side effects or changes of clinical relevance impulse rate, blood pressure, ECG or laboratory test results.

Comparisons relevant to Canada

Albuterol vs fenoterol

Yang and colleagues67 examined 13 (11 male) COPD patients' response to exercise and found no significant difference in cardiopulmonary response between nebulized fenoterol or salbutamol (2 mg) 30 minutes given prior to exercise. They did note that plasma potassium was significantly lower after exercise after fenoterol compared to the saline control and salbutamol.

Among predominantly male patients with COPD, Tandon63 found no differences in bronchodilator efficacy between these drugs, but heart rates increased significantly more with fenoterol than salbutamol after 7 to 13 puffs.

Among 24 adults with asthma53 (mean age 29 years, 83% male), median duration of 15% bronchodilation was 6 hours for fenoterol (320 ug) and 3.5 hours for albuterol (180ug) (p<0.01) with no significant changes in heart rate, blood pressure and ECG changes in either treatment group. Mild adverse symptoms were noted in 11 of 24 patients on fenoterol; none were noted with albuterol.

Among children with chronic asthma age 7 to 13 years (15 of 16 were male), no significant differences were noted between salbutamol and fenoterol for the time of response to the medications, maximal effect and duration. There was no increase in heart rate and no adverse events reports.49

Metaproterenol vs terbutaline

Peacock and colleagues87 examined these comparisons as noted above (albuterol vs metaproterenol comparison).

Fenoterol vs terbutaline vs albuterol

In a small, cross-over study66 of eight men and two women, fenoterol, salbutamol and terbutaline all produced similar bronchodilation. However, the increase in heart rate, QTc interval and tremor and fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline.

Race

For the most part, race or ethnicity data were not provided in studies. No studies were exclusively of African-American or other minority populations; two studies compared albuterol vs levalbuterol in predominantly African-American, pediatric asthma patients,68, 79 and one study examined asthmatic adults.77

Albuterol vs levalbuterol

In an RCT in the emergency department,68 a primarily African American population of children (86% Black) age 1 to 8 years (n=482) received either 2.5 mg of albuterol or 1.25 mg levalbuterol via nebulizer every 10 minutes to a maximum of six doses. Hospitalization rate, the primary outcome, was significantly lower in the levalbuterol group (36%) than in the albuterol group (45%) (p=0.02). Length of hospital stay was not different in the two groups (p=0.63) and no significant adverse events occurred in either group.

In a similar RCT in the emergency department,79 129 children aged 2 to 14 years (83% African American), there were no significant differences between treatment group for the primary outcome of clinical asthma score and the FEV1 after 1, 3 and 5 treatments. There were also no differences in the number of treatments, length of emergency room care, rate of hospitalization, and changes in heart rate, respiratory rate, and oxygen saturation. One child receiving albuterol had tachycardia >200 beats per minute. Adverse events were not significantly different in the two groups.

Comorbidities

Only one included study specifically examined comorbidities.24 Many COPD trials indicated the presence of comorbidities, but data were not presented that permitted subgroup analyses of specific conditions.

Among 12 COPD patients with preexisting cardiac arrhythmias, Cazzola and colleagues24 noted a greater increase in heart rate with formoterol 24ug (10 beats per minute 4 hours after treatment) compared to salmeterol 50 ug (5.5 beats per minute) post inhalation of a single dose. They also observed more supraventricular or ventricular premature beats after formoterol 24ug, although between-group statistics were not presented.

Copyright © 2006, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK10436
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