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My original response to Dr Salpeter’s debate (1) was based on a desire to engage her in a discussion related to the safety of beta2- agonists in the management of asthma and chronic obstructive pulmonary disease (COPD) using an evidence based platform of the best available studies. Unfortunately, Dr saltpeter begins her response by suggesting that my comments are tempered by a serious bias toward promoting long- acting beta2-agonist (LABA) use, in particular formoterol, since I have affiliations with pharmaceutical companies that manufacture formoterol and because I raise the possibility that safety concerns focus primarily around salmeterol use in asthma. I would like to reassure Dr Salpeter that my comments are guided by scientific evidence and that my research work has not been restricted to formoterol.
In one of the few real world studies (randomized, double-blind) involving salmeterol, another LABA (2) (sponsored by GlaxoSmithKline), we showed that the frequency of severe exacerbations (primary endpoint) among asthmatic patients (n=911) using inhaled corticosteroids was similar between placebo and salmeterol over a six month period. My comments that safety concerns with respect to LABA use in asthma management centre around salmeterol relate to two (3, 4) large, double–blind, randomized studies (with more that 50,000 patients) that were designed to assess the safety of salmeterol; in particular whether mortality is increased with salmeterol. The main conclusion of the first trial (3) Serevent Nationwide Surveillance (SNS) Study (n = 25,000) was that more deaths occurred with salmeterol, but compared to salbutamol, this result was not statistically significant. In the Salmeterol Multicentre Asthma Trial (SMART) (4) which included more that 25, 000 patients, while there were no differences in respiratory-related deaths or life-threatening experiences between placebo and salmeterol, there was an excess in respiratory related deaths (relative risk, 2.16 [95% CI, 1.06 to 4.41] and in asthma related deaths (relative risk, [4.37 95% CI, 1.25 to 15.34]) among patients receiving salmeterol. Recently, Sears et al. (5) investigated whether formoterol use increased asthma mortality and non-fatal asthma related serious adverse events (SAE) among individuals (94% using ICS) participating in AstraZeneca sponsored randomized, controlled, parallel- group trials exceeding one month; involving formoterol as maintenance, reliever or both with ICS or as monotherapy. Sears et al. (5) identified 71,148 patients from 69 trials. In the formoterol exposed patients mortality was 0.34 per 1000 patient years compared to mortality with patients not exposed to LABA in three large asthma trials (0.55 per 1000 patient years). Asthma related SAEs were significantly reduced with formoterol exposure versus non-LABA treatment (RR 0.83; 95%CI: 0.69- 1.00). Higher doses of formoterol were not associated with increased risk compared to lower doses (36 µg vs. 18 µg vs. 9 µg total daily delivered dose). In patients not using ICS deaths and SAE were slightly (non- significant) higher among patients using formoterol. The study by Wolfe et al. (6) (that included 2,085 patients) suggests that treatment with formoterol 24 µg bid was not associated with an increase in serious asthma exacerbations compared with lower doses of formoterol or placebo. Of interest, Wolfe et al. (6) reported significantly fewer exacerbations requiring systemic corticosteroid treatment with formoterol 12 µg BID plus on demand (4.4%, 23 of 517) vs. placebo 8.8% 45 of 514, P < 0.0057). Furthermore, in the RELIEF (open label) trial (7) (children and adults, n=18,124) formoterol used as rescue therapy (an option that cannot be exploited with salmeterol due to its slower onset of action) had a similar safety profile to salbutamol and was associated with fewer asthma exacerbations. Finally, in both the FACET (8) and OPTIMA (9) trials (n approximately 3300 patients for both trials) the addition of formoterol in non-steroid-naive patients was associated with a reduction in severe exacerbations compared to higher doses of ICS. There are few prospective trials (10) showing a reduction in severe exacerbations (where severe exacerbations was a primary endpoint) when salmeterol is added to ICS therapy. Recent data suggest that the combination of formoterol and budesonide (in a single inhaler) used as both maintenance and rescue therapy (11) is superior to fixed dose therapy with the combination of salmeterol and fluticasone (in a single inhaler) and a short-acting beta2- agonist for rescue. There is also good evidence that formoterol when used as rescue therapy may provide additional benefits, especially if budesonide is used concomitantly in a singe inhaler (12). Large head-to- head trials comparing formoterol to salmeterol in the chronic management of asthmatics using ICS are needed to evaluate differences in therapeutic benefit. The evidence (mainly from randomized controlled trials) outlining the efficacy and safety of formoterol with concomitant ICS use is robust and contributes significantly to recommendations on LABA use as outlined in current national and international guidelines (13, 14). As a family physician with a very busy lung practice I feel very comfortable given the information outlined above that my clinical decisions are influenced by some of the best available evidence as defined in current guidelines (13, 14). I should note that a number of experts who are members of the Canadian Asthma Guideline Group highlight (15) important concerns about the Saltpeter data (16) in terms of its applicability to current practice since pivotal trials examining the benefit of adding LABAs to ICS were not included; a scenario which could introduce serious publication bias.
The fact that the FACET (8) trial did not have a placebo arm as defined by Salpeter (16) does not dismiss the need to explain why despite the observation of tolerance with formoterol use (to bronchodilation) patients receiving formoterol and ICS experienced fewer severe exacerbations compared to patients receiving ICS and as needed SABA.
Saltpeter indicates that the TORCH trial (17) showed an increase in COPD deaths in the salmeterol group (n = 93) versus (n = 91) in the placebo group (P = 0.93) and in deaths due to pulmonary causes, n = 74 and 80 for placebo and salmeterol groups respectively; the latter findings were also not significant. What Dr Salpeter does not discuss is the fact that the TORCH trial was powered to detect differences in mortality between study groups and none was found. Instead, Saltpeter uses pooled historical data (18) and non-significant differences among prospective data sets to defend a position that has yet to be supported in a single, randomized, placebo-controlled, mortality trial.
Much has been learned from the TORCH trial but many important questions remain. In order to confirm the validity of the Salpeter position large randomized controlled mortality trials comparing beta2- agonists to anticholinergic therapy are needed. The fact that Canadian Family Physician invited a debate on the safety of beta2-agonists in obstructive pulmonary disease should not be cause for alarm given the prospective evidence available at the present time confirming the benefits of such therapy. We should not be lead to believe that a lack of affiliation with the pharmaceutical industry necessarily adds credibility to one’s opinion. Our clinical judgment and decision-making should always be guided by the best available evidence derived from critical appraisal strategies. Given the clear global consensus on the safety and benefits of LABAs when used appropriately in asthma and COPD, I remain concerned that the Salpeter controversy will serve to distract family physicians from utilizing appropriate therapeutic interventions.
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