http://www.healthsentinel.com/org_news.php?event=org_news_print_list_item&id=116
Roman Bystrianyk, "Beta-Agonists may cause thousands of asthma-related
deaths each year", Health Sentinel, January 2, 2007,

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