Long-acting beta-agonists are part of a group of medications call bronchodilators which act to open up constricted airways. Long-acting beta-agonists, such as salmeterol (Serevent) and formoterol (Foradil) are used to control moderate to severe asthma and prevent nighttime symptoms. Salmeterol is one of the most widely prescribed medications in the world, with an estimated 3.5 million adults treated in the United States in 2004.
Advair is the brand name drug combining fluticasone (a steroid) and salmeterol to prevent wheezing, shortness of breath, and breathing difficulties caused by asthma. Made by GlaxoSmithKline Advair contains salmeterol that is found alone in Serevent. In 2004, Advair's U.S. sales reached $2.4 billion, and its worldwide sales of more than $4.5 billion made it the third best selling drug in the world.
But just how safe are these products in treating asthma?
In May 2005, the FDA requested manufacturers of these medications (Advair Diskus, Foradil Aerolizer, and Serevent Diskus) to update their product warning labels that these products “increase the chance of severe asthma episodes, and death when those episodes occur.”
However, controversy has surrounded the use of beta-agonists in asthma patients ever since their introduction over 50 years ago. Numerous studies over many years have shown regular use of beta-agonists are associated with tolerance to the drug’s effects and worsening of disease control. Observational studies have consistently shown that the risk of life threatening and fatal asthma attacks increase with the use of these medications.
After receiving post marketing reports of several asthma-related deaths associated with Salmeterol a Multi-center Asthma Research Trial (SMART) was undertaken. The study followed more than 26,000 participants for 6 months and found a 4-fold increased risk for asthma-related deaths.
Beta-agonists are also widely used to treat Chronic Obstructive Pulmonary Disease, or COPD. A recent meta-analysis pooled the results of 22 randomized trials, which followed more that 15,000 participants with COPD. The study found that beta-agonists increased respiratory deaths by more than 2-fold.
In November 2004, whistleblower Dr. David Graham indicated that salmeterol (Serevent, A&H) was one of the drugs currently on the market that may be endangering patients. The other drugs Dr. Graham named were the weight loss drug sibutramine (sold as Reductil in Britain and Meridia in the United States), the lipid lowering drug rosuvastatin (Crestor; made by AstraZeneca), and the acne drug isotretinoin (Roaccutane; Roche).
A recent study published in Annals of Internal Medicine, performed a meta-analysis to determine the effect of long-acting beta-agonists on severe asthma exacerbations requiring hospitalization, life-threatening asthma attacks, and asthma-related deaths. They analyzed salmeterol and formoterol in children and adults examining all randomized, double-blind, placebo-controlled trials on long-acting beta-agonist use in patients with asthma that were published between 1966 and December 2005. The authors were able to pool the results of 19 trials with 33,826 participants.
The authors found that “long-acting beta-agonists increased the risk for hospitalization for an asthma exacerbation, life-threatening asthma attacks, and asthma-related deaths compared with placebo. Hospitalizations increased among adults and children with salmeterol and formoterol.”
Regular use of beta-agonists has been shown to increase bronchial hyperactivity regardless of some degree of bronchodilation. This effect along with the reduction in response to later rescue beta-agonist use “may worsen asthma control without giving any warning of increased symptoms.”
The authors determined that because these medications are so widely used throughout the United States and the world that “salmeterol may be responsible for approximately 4,000 of the 5,000 asthma-related deaths that occur in the United States each year.”
Asthma deaths increased worldwide in the 1960s when beta-agonists were introduced onto the market. In New Zealand asthma related deaths increased when the beta-agonist drug fenoterol was introduced. Asthma related deaths rapidly decreased when use of the drug was severely cut back. “If long-acting beta-agonists were removed from the market in the United States, we might witness a reduction in asthma mortality rates here.”
The authors conclude, “long-acting beta-agonists use increases the risk for hospitalizations due to asthma, life-threatening asthma exacerbations, and asthma-related deaths. Similar risks are found with salmeterol and formoterol and in children and adults. Concomitant inhaled corticosteroids do not adequately protect against the adverse effects.”
“The use of long-acting beta-agonists could be associated with a clinically significant number of unnecessary hospitalizations, intensive care unit admissions, and deaths each year. Black box warnings on the labeling for these agents clearly outline the increased risk for asthma-related deaths associated with their use, but these warnings have not changed prescribing practices of physicians. This information could be used to reassess whether these agents should be withdrawn from the market.”
Source: Annals of Internal Medicine, June 2006