From the Journals

As-needed budesonide-formoterol prevented exacerbations in mild asthma

 

Key clinical point: As-needed budesonide-formoterol (Symbicort) prevented exacerbations in patients with mild persistent asthma.

Major finding: In the SYGMA1 trial, the regimen outperformed as-needed terbutaline for asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (RR, 0.36; 95% CI, 0.27-0.49). In SYGMA2, the regimen was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% confidence limit, 1.16).

Study details: SYGMA1 and SYGMA2, randomized phase 3 trials of 8,012 patients aged 12 years and older with mild persistent asthma.

Disclosures: AstraZeneca provided funding. For SYGMA1, Dr. Byrne disclosed ties to AstraZeneca, Novartis, GlaxoSmithKline, Medimmune, and Genentech. For SYGMA2, Dr. Bateman disclosed ties to AstraZeneca, Novartis, Cipla, Vectura, Boehringer Ingelheim, and a number of other pharmaceutical companies.

Sources: O’Byrne PM et al. N Engl J Med. 2018 May 17;378(20);1865-76. Bateman ED et al. N Engl J Med. 2018 May 17;378(20):1877-87.

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‘Two out of three ain’t bad’

In the SYGMA1 and SYGMA2 trials, as-needed budesonide-formoterol (Symbicort) prevented exacerbations and loss of lung function, the two worst outcomes of poorly controlled asthma, concluded Stephen C. Lazarus, MD, in an editorial accompanying the studies in the New England Journal of Medicine.

“As-needed treatment was similar, or at least noninferior, to regular maintenance therapy with inhaled glucocorticoids with regard to the prevention of exacerbations, and exacerbations are the main contributor to loss of lung function, death, and cost,” wrote Dr. Lazarus.

Patients typically received only 17%-25% as much inhaled glucocorticoid as did those on maintenance budesonide, which would help prevent side effects and would make the regimen more acceptable to “glucocorticoid-averse patients,” he added. Another benefit to patients with mild persistent asthma using as-needed budesonide-formoterol instead of inhaled glucocorticoid maintenance therapy is that it would result in nearly $1 billion in cost savings in the United States yearly.

Budesonide-formoterol did not control symptoms as well as did maintenance budesonide, but patients might accept “occasional mild symptoms and inhaler use if it [freed] them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations,” he concluded. “For these patients, ‘Two out of three ain’t bad!’ ”

Dr. Lazarus is in the department of medicine and at the Cardiovascular Research Institute, University of California, San Francisco. He reported having no conflicts of interest. This comments are from his editorial (N Engl J Med. 2018 May 17. doi: 10.1056/NEJMe1802680).


 

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Formoterol plus budesonide prevented exacerbations when inhaled as needed by patients with mild persistent asthma, according to the results of two large, double-blind, 52-week, randomized phase 3 trials.

In the SYGMA1 (Symbicort Given as Needed in Mild Asthma) trial, the regimen outperformed as-needed terbutaline in terms of asthma control (34.4% vs. 31.1% of weeks; P = .046) and exacerbations (rate ratio, 0.36; 95% confidence interval, 0.27-0.49). In the SYGMA2 study, it was noninferior to twice-daily budesonide for preventing severe exacerbations (RR, 0.97; upper one-sided 95% CI, 1.16). The findings were published in two reports in the New England Journal of Medicine.

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Asthma often is undertreated because many patients adhere poorly to maintenance glucocorticoids, noted Paul M. O’Byrne, MD, of McMaster University in Hamilton, Ont., and his associates from SYGMA1 (NCT02149199). Instead, patients often rely on short-acting beta2-agonists for symptom control, but these drugs don’t stop exacerbations or treat underlying inflammation. “One potential strategy to address these issues is the use of a combination of a fast-acting beta2-agonist and an inhaled glucocorticoid taken only on an as-needed basis,” the researchers wrote.

Accordingly, they randomly assigned 3,849 patients aged 12 years and up who had mild persistent asthma (mean forced expiratory volume in 1 second [FEV1] before bronchodilator use, 84% of predicted value) to receive one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed, twice-daily placebo plus budesonide-formoterol (200 mcg of budesonide and 6 mcg of formoterol) used as needed, or maintenance twice-daily budesonide (200 mcg) plus as-needed terbutaline (0.5 mg), all for 52 weeks.

In the final analysis of 3,836 patients, annual rates of severe exacerbations were 0.20 with terbutaline, significantly worse than with budesonide-formoterol (0.07) or maintenance budesonide (0.09). Using budesonide-formoterol (Symbicort) as needed improved the odds of having well-controlled asthma by about 14%, when compared with using terbutaline as needed (odds ratio, 1.14; 95% CI, 1.00-1.30; P = .046).

Although maintenance budesonide controlled asthma best (44.4% of weeks; OR vs. budesonide-formoterol, 0.64; 95% CI, 0.57-0.73), 21% of patients did not adhere to it, the researchers reported. “Patients are often more concerned [than their health care providers] about adverse effects of inhaled glucocorticoids, even when low inhaled doses are used,” they wrote. Notably, the budesonide-formoterol as-needed group received a median daily dose of only 57 mcg inhaled glucocorticoid, 17% of that received by the budesonide maintenance group.

In SYGMA2 (NCT02224157), 4,215 patients with mild persistent asthma aged 12 years and up were randomly assigned to receive either twice-daily placebo plus as-needed budesonide-formoterol or twice-daily maintenance budesonide plus as-needed terbutaline. Doses were the same as in the SYGMA1 trial. The regimens resembled each other in terms of severe exacerbations (annualized rates, 0.11 and 0.12, respectively) and time to first exacerbation, even though budesonide-formoterol patients received a 75% lower median daily dose of inhaled glucocorticoid, reported Eric D. Bateman, MD, of the University of Cape Town, South Africa, and his associates.

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