Panel Votes Against Two Drugs for Asthma

By GARDINER HARRIS

ROCKVILLE, Md., 12 dec 2008 — A panel of federal drug experts recommended on Thursday that the drugs Serevent and Foradil be banned from use in the treatment of asthma, but the experts said that Advair and Symbicort, which are far more popular, should continue to be used.

The experts, gathered by the Food and Drug Administration, said that too many doctors used Serevent and Foradil inappropriately, and that asthmatic patients were often fooled by their own symptoms and used them incorrectly. For children, the experts voted unanimously to ban the use of Serevent and Foradil. For adults, the panel voted 17 to 10 to ban Serevent and 18 to 9 to ban Foradil.

Serevent and Foradil widen lung airways but increase the risks of death unless they are paired with a steroid. The two drugs’ labels already warn doctors to pair them with steroids, but half of patients do not get a steroid. And even when patients get a steroid, many fail to take it.

GlaxoSmithKline, the maker of Serevent, and Novartis, the maker of Foradil, argued that doctors wanted the freedom to mix and match these kinds of drugs with steroids as they wish. But Dr. Jesse Joad, a panel member and a pediatrician from University of California Davis Medical Center, said she did not “want to give a drug that is making the disease you’re treating worse.”

Both Serevent and Foradil are also approved to treat chronic obstructive pulmonary disorders like emphysema, so even if the F.D.A. follows the panel’s advice, the drugs will remain on the market.

Asthma is caused when airways within the lungs spasm and swell, restricting the supply of oxygen. The two primary treatments are steroids, which reduce swelling, and beta agonists, which treat spasms. Rescue inhalers usually contain albuterol, a short-acting beta agonist.

Serevent and Foradil are longer-acting beta agonists intended to prevent attacks. Used without a steroid, however, these drugs have been shown to increase the risks of more severe attacks. Advair and Symbicort pair these longer-acting beta agonists with steroids.

The panel voted unanimously that Advair should continue to be used in asthmatic adults and supported its use in adolescents by 23 to 3 and in children by 13 to 11. The panel also voted unanimously to support Symbicort’s use in asthmatic adults and 20 to 5 to support its use in adolescents. Symbicort is not approved for use in children.

Earlier, some top F.D.A. safety experts recommended that all four drugs should be banned from treating asthma in both adults and children, while other F.D.A. experts said the drugs’ benefits outweighed their risks. The agency has struggled for years to balance the risks and benefits of the medications, and this week’s advisory committee was the fifth to tackle the medicines.

Like other drug-safety controversies, the debate largely pits those who see the controversy through the eyes of a single patient against those who study populations. Since the drugs may lead to one death in somewhere between 700 and 4,000 patients, few doctors have had a patient who died from using the drugs. So most doctors focus on the benefits of the drugs, which allow many of their patients to play sports, go to work or lead normal lives.

Among the supporters of the drugs was Anne Dorsey of Baltimore, who described the night that her 13-year-old son, Julian, nearly died from an asthma attack. Julian spends much of his life in the hospital and is now taking Advair.

“I have to ask you not to let him perish” by banning the drugs, Ms. Dorsey said. Then Julian stepped to the microphone. In a reedy voice, he said that Advair had cut in half the time he spends in the hospital. “Life got a lot easier,” he said, “and without Advair, I don’t know what I’d do.”

The American Academy of Pediatrics, the American Academy of Allergy Asthma and Immunology and the American College of Allergy Asthma and Immunology all support the continued use of the medicines.

The F.D.A. experts who recommended that the drugs no longer be used in asthma tend to view such issues on a population basis. With more than three million asthmatics in the country taking the medicines, the drugs’ risks could cause thousands of deaths each year.

For these experts, long-acting beta agonists — while they may make patients feel mildly better — have few concrete benefits that would justify so many deaths. And sudden death is a risk that, even when patients are warned about it, is not something they can control by behaving differently.

Asthma is a highly unpredictable disease that can lull patients into complacency, and the effects of the medicines can worsen this problem. Severe, life-threatening attacks can strike out of the blue, and milder symptoms may not predict more severe ones.

The beta agonists — by relaxing bronchial spasms — treat mild symptoms and make patients feel better immediately. Feeling better, these patients — if they are taking beta agonists and steroids separately — may decide against taking the steroids since steroids have few immediate benefits. Patients who are prescribed both drugs separately get fewer refills of the steroid than of the beta agonists. Such patients leave themselves vulnerable to severe attacks and death.

Dr. Sean P. Hennessy, a panel member from the University of Pennsylvania, said that the F.D.A. should withdraw its approval of Serevent and Foradil in the treatment of asthma to prevent patients from taking these medicines without steroids. And he called for Glaxo to begin a large safety study of Advair.

“Given the problems and the nearly $8 billion in revenue earned from Advair, this seems imminently plausible,” Dr. Hennessy said.

Dr. Fernando Martinez, director of the Arizona Respiratory Center at the University of Arizona, noted that far too many patients whose conditions could be treated adequately with steroids alone were instead receiving Advair or Symbicort, which are riskier and more expensive. He said the drugs’ makers must educate doctors better, but he said “it would be irresponsible to withdraw these medicines” because they improve patients’ lives.

Doctors face difficult choices with children whose asthma remains uncontrolled with low-dose steroid treatment. If they increase the steroid dose, the risks include stunted growth, acne, greater vulnerability to infections and affects to skin, eyes and bone. If they add a long-acting beta agonist, the risks of death, although still small, increase

Warning Given on Use of 4 Popular Asthma Drugs, but Debate Remains

By GARDINER HARRIS
WASHINGTON, 07 dec 2008 — Two federal drug officials have concluded that asthma sufferers risk death if they continue to use four hugely popular asthma drugs — Advair, Symbicort, Serevent and Foradil. But the officials’ views are not universally shared within the government.
The two officials, who work in the safety division of the Food and Drug Administration, wrote in an assessment on the agency’s Web site on Friday that asthma sufferers of all ages should no longer take the medicines. A third drug-safety official concluded that Advair and Symbicort could be used by adults but that all four drugs should no longer be used by people age 17 and under.
Dr. Badrul A. Chowdhury, director of the division of pulmonary and allergy products at the agency, cautioned in his own assessment that the risk of death associated with the drugs was small and that banning their use “would be an extreme approach” that could lead asthmatics to rely on other risky medications.
Once unheard of, public disagreements among agency experts have occurred on occasion in recent years. The agency is convening a committee of experts on Wednesday and Thursday to sort out the disagreement, which has divided not only the F.D.A. but also clinicians and experts for more than a decade.
Sudden deaths among asthmatics still clutching their inhalers have fed the debate. But trying to determine whether the deaths were caused by patients’ breathing problems or the inhalers has proved difficult.
The stakes for drug makers are high. Advair sales last year were $6.9 billion and may approach $8 billion this year, making the medication GlaxoSmithKline’s biggest seller and one of the biggest-selling drugs in the world. Glaxo also sells Serevent, which had $538 million in sales last year. Symbicort is made by AstraZeneca and Foradil by Novartis.
Whatever the committee’s decision, the drugs will almost certainly remain on the market because even the agency’s drug-safety officials concluded that they were useful in patients suffering from chronic obstructive pulmonary disease, nearly all of whom are elderly.
Dr. Katharine Knobil, global clinical vice president for Glaxo, dismissed the conclusions of the agency’s drug-safety division as “not supported by their own data.” Dr. Knobil said that Advair was safe and that Serevent was safe when used with a steroid.
Michele Meeker, a spokeswoman for AstraZeneca, said that the F.D.A.’s safety division improperly excluded most studies of Symbicort in its analysis, and that a review of all of the information shows that the drug does not increase the risks of death or hospitalization.
Dr. Daniel Frattarelli, a Detroit pediatrician and member of the American Academy of Pediatrics’s committee on drugs, said that he was treating children with Advair and that his committee had recently discussed the safety of the medicines.
“Most of us felt these were pretty good drugs,” Dr. Frattarelli said. “I’m really looking forward to hearing what the F.D.A. committee decides.”
About 9 percent of Advair’s prescriptions go to those age 17 and under, according to Glaxo. Ms. Meeker could not provide similar figures for Symbicort.
In 1994, Serevent was approved for sale, and the F.D.A. began receiving reports of deaths. A letter to the New England Journal of Medicine described two elderly patients who died holding Serevent inhalers. Glaxo warned patients that the medicine, unlike albuterol, does not work instantly and should not be used during an attack.
In 1996, Glaxo began a study of Serevent’s safety, but the company refused for years to report the results publicly. In 2001, the company introduced Advair, whose sales quickly cannibalized those of Serevent and then far surpassed them.
Finally in 2003, Glaxo reported the results of its Serevent study, which showed that those given the medicine were more likely to die than those given placebo inhalers. Glaxo said problems with the trial made its results impossible to interpret.
Asthma is caused when airways within the lungs spasm and swell, restricting the supply of oxygen. The two primary treatments are steroids, which reduce swelling, and beta agonists, which treat spasms. Rescue inhalers usually contain albuterol, which is a beta agonist with limited duration. Serevent and Foradil are both beta agonists but have a longer duration than albuterol and were intended to be taken daily to prevent attacks.
Advair contains Serevent and a steroid. Symbicort, introduced last year, contains Foradil and a steroid. In the first nine months of this year, Symbicort had $209 million in sales.
The problem with albuterol is that it seems to make patients’ lungs more vulnerable to severe attacks, which is why asthmatics are advised to use their rescue inhalers only when needed. The long-acting beta agonists may have the same risks.
But drug makers say this risk disappears when long-acting beta agonists are paired with steroids. The labels that accompany Serevent and Foradil instruct doctors to pair the medicines with an inhaled steroid.

How aspirin could help women fight asthma

By JENNY HOPE
Taking a low dose of aspirin every other day could ward off asthma for women, say researchers.
A study found that a group of older women taking aspirin regularly developed 10 per cent fewer new cases than expected.
It is the latest in a string of discoveries of beneficial effects from the drug, which has been shown to cut the risk of heart attacks, stroke, some cancers and dementia.
More than five million Britons suffer from asthma, which claims 1,400 lives a year here.
The American study, detailed in the medical journal Thorax, was based on monitoring the health of 40,000 women of 45 and over.
They were randomly assigned to take either 100mg of aspirin every other day or a placebo.
In the group taking aspirin 872 new cases were diagnosed compared with 963 among those taking a placebo.
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The effect persisted even after taking account of factors such as age and smoking, although aspirin did not lessen the risk in obese women.
Study leader Dr Tobias Kurth, from Brigham and Women's Hospital in Massachusetts, said the biological mechanism involved was unknown and further trials were necessary.
The team warned that existing asthma patients would not benefit.
Previous research in male doctors found aspirin cut the risk of asthma by 22 per cent.
For all its benefits, aspirin can have side effects ranging from dizziness to stomach pain and bleeding.
Some people are hypersensitive to it and cannot tolerate even small amounts.
It may also be unsuitable for people with uncontrolled high blood pressure, liver or kidney disease, peptic ulcer or conditions that may cause internal bleeding.

IDSA: More Data Support H. pylori­-Asthma Link

SAN DIEGO, Oct. 5 -- Eradication of Helicobacter pylori may have had the unintended consequence of unleashing an asthma threat even as the risk of gastric ulcer and cancer declined, results of a study reported here suggest.
H. pylori negativity predicted a significantly increased risk of early-onset asthma, asthma recurrence, and asthma severity in children, Martin J. Blaser, M.D., of New York University, said at the Infectious Diseases Society of America meeting.
H. pylori also had an inverse association with a history of wheezing, allergic rhinitis, eczema, dermatitis, and rash, he said.
"We started out just looking at asthma, but because we had data on all these other conditions, we decided to look at them as well," said Dr. Blaser. "What we found is that H. pylori had an inverse association with all of them, all of these essentially allergic disorders."
"The findings are consistent with the hypothesis that H. pylori protects against all of these conditions, and therefore, the disappearance of H. pylori is fueling, in part, the rise in these conditions. The data don't prove that, but they are consistent with the hypothesis."
Investigators explored the hypothesis using data from the 1999-2000 National Health and Nutrition Examination Survey, the most recent version of the survey to include test results for H. pylori. The NHANES database included information on 3,327 participants ages three to 19.
Comparison of H. pylori status and asthma history showed that participants who tested positive for the bacterium were 35% less likely to have any history of asthma (OR = 0.65; 95% CI = 0.43-1.01) and 44% less likely to have asthma onset before age five (OR = 0.56; 95% CI - 0.37-0.87).
Among participants ages three to 13, H. pylori seropositivity was associated with a 53% reduction in the relative risk of asthma (OR = 0.56; 95% CI = 00.37-0.87).
"Our findings are consistent with the hypothesis that H. pylori protects against asthma, possibly by priming the immune system in some way," said Dr. Blaser.
The reduced likelihood of wheezing, allergic rhinitis, eczema, dermatitis, and rash suggests H. pylori has a broader protective role that encompasses a variety of manifestations of atopia, he added.
The findings also support the hypothesis that H. pylori, as the dominant species when present in the stomach, affords natural protection against gastroesophageal reflux disease and, by extension, conditions associated with GERD. Dr. Blaser noted that GERD and asthma have a well-documented association.
The results also are consistent with findings that Dr. Blaser and colleagues reported earlier this year (Arch Intern Med 2007; 167:821-827). Also based on NHANES data, that study demonstrated a significant inverse association between H. pylori seropositivity and asthma history in adults, particularly childhood-onset asthma. (See: H. pylori May Offer Kids Asthma Protection).
Dr. Blaser reported no conflicts of interest. Primary source: Infectious Diseases Society of AmericaSource reference: Chen Y, Blaser MJ. "Helicobacter pylori colonization is inversely associated with childhood asthma." Infectious Diseases Society of American Annual Meeting. Oct. 4-7, San Diego. Final Program and Abstracts. Abstract LB-1.

New Asthma Guidelines Emphasize Disease Control and Patient Empowerment

BETHESDA, Md., Aug. 30 --Emphasizing that asthma affects different patients in different ways, the National Asthma Education and Prevention Program has issued new evidence-based guidelines on the disease.
The guidelines include a new emphasis on patient involvement and control of environmental triggers of asthma.
The guidelines are based on evidence from research and clinical experience over the past decade into the mechanisms underlying airway inflammation and into better methods for control, said William Busse, M.D., of the University of Wisconsin at Madison, chairman of the expert panel that drew up the guidelines.
Regarding medication, the guidelines continue the established stepwise approach to asthma control, but with revised and expanded management charts based on three age groups: birth to four years, five to 11, and 12 and older.
The addition of the five to 11 group is a recognition of differing drug responses between children and adults, Dr. Busse said.
The report reaffirms that patients with persistent asthma require both long-acting control medications and acute rescue therapies as needed, with inhaled corticosteroids recognized as the most effective agents for chronic control in all age groups.
The guidelines also include new recommendations on the use of leukotriene receptor antagonists and cromolyn sodium for chronic asthma control, long-acting beta agonists as adjunctive therapy with inhaled corticosteroids; omalizumab (Xolair) for severe asthma, and on the use of albuterol, levalbuterol, and corticosteroids for acute exacerbations.
The guidelines, weighing in at 487 pages, build on earlier iterations from 1991, 1997 and a 2004 update, but with several key differences, Dr. Busse said. These differences include:
Further substantiation of the role of inflammation in asthma, with recognition of phenotypic differences resulting in variability in patterns of inflammation
Recognition of genetic and environmental interactions in asthma expression, with allergic reactions identified as an important environmental factor. Emerging evidence also points to the role of viral respiratory infections.
Understanding that "the onset of asthma for most patients begins early in life with the pattern of disease persistence determined by early, recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of asthma."
A finding that anti-inflammatory therapy as currently practiced does not appear to prevent progression of the underlying disease severity.
"The new scientific evidence that makes up the guidelines that we're releasing today point to one truth: asthma control is achievable for nearly every patient," said Elizabeth Nabel, M.D., director of the National Heart, Lung, and Blood Institute.
"With appropriate medical care, healthy environments, and well-informed and empowered patients asthma can be controlled and patients can lead full active lives," she said in a media briefing.
The Expert Panel Report 3, as the guidelines are known, focus on four key areas of asthma diagnosis and treatment: assessment and monitoring, patient education, control of environmental factors and other modifiable conditions that can affect asthma, and medications.
The guidelines call for assessing and monitoring asthma with multiple measures of asthma severity, including frequency and intensity of symptoms, lung function, and limitations of daily activities as well as future risk (risk of exacerbations, progressive loss of lung function, or adverse effects from medications). The guidelines emphasize that some patients with intermittent asthma may still be at high risk for frequent severe exacerbations.
The guidelines also stress the importance of educating patients about self-assessment of symptoms and management of asthma, including use of a written action plan with instructions for daily treatment as well as acute and chronic symptoms. New recommendations emphasize bringing asthma education into community setting such as schools, pharmacies, and homes.
The report includes recommendations on control of environmental asthma triggers, with an emphasis on multiple approaches to achieving control, and expands information on treatment of co-morbidities such as rhinitis and sinusitis, gastroesophageal reflux, overweight or obesity, obstructive sleep apnea, stress, and depression.
The report also describes promising new avenues for research into improving asthma management, including tailoring treatment to the asthma phenotype and genotype of individual patients.
"Research is beginning to help us identify genes that influence how well certain patients respond to certain asthma medications," said James Kiley, Ph.D., director of the NHLBI Division of Lung Diseases. "This information is helping us move toward providing personalized treatment for asthma based on a patient's individual characteristics."
A summary report will be released on Oct. 17.
The report, titled Expert Panel Report 3:Guidelines for the Diagnosis and Management of Asthma, is available free of charge at the NHLBI web sitePrimary source: National Heart, Lung, and Blood InstituteSource reference: Expert Panel Report 3:Guidelines for the Diagnosis and Management of Asthma