Sunday, December 23, 2012

Aspirin and Asthma

If you have asthma, you may at some point have been told by a doctor never to take aspirin. At the same time we read about all the benefits of aspirin, including prevention of heart attacks and strokes and most recently as an aid in treating some types of colon cancer. Is it true that you need to forego these health benefits because you have asthma?

The brief answer is: in most instances, no. In most persons with asthma (probably at least 95%), aspirin acts in the same way that it does for everyone else. It alleviates pain, relieves headache, and reduces fever without any unusual side effects. The doctor’s admonition to avoid aspirin came from the observation that in a small subgroup of persons with asthma, perhaps 3-5%, aspirin provokes an asthma attack, sometimes quite a severe attack, with associated nasal congestion and sometimes abdominal discomfort. Asthma sufferers need to avoid aspirin and all aspirin-containing products only if their unique body chemistry causes them to suffer an asthma (and sinus) attack after aspirin ingestion.

The long answer is more complicated (of course!). Here are three additional points worth noting.

1. Persons with asthma in whom aspirin causes an asthma attack will develop the same severe reaction if they were to take ibuprofen (Motrin), naproxen (Aleve), or any similar category of medicine (called non-steroidal anti-inflammatory drugs or NSAIDs). They do not have a true “allergy” to aspirin but rather a chemical sensitivity or intolerance to any of this family of medications that act to block the protein in our bodies called cyclooxygenase 1.

2. Children with asthma do not experience “aspirin-exacerbated respiratory disease” or AERD, as this unique reaction to aspirin is now called. It only emerges later in life. There is no blood or breath test that allows your doctor to determine whether you are aspirin intolerant or not. The diagnosis is usually made by direct experience – taking an aspirin or ibuprofen or naproxen tablet and experiencing an attack of your asthma 30-90 minutes later.

3. Help is available. The Allergy group at Brigham and Women’s Hospital has special interest and expertise in this area. For the diagnosis of aspirin intolerance, it is possible to undergo a carefully structured “aspirin challenge” in a supervised medical setting (taking initially very small doses of aspirin and observing for an asthmatic reaction). For treatment of aspirin intolerance – besides avoidance of aspirin and all chemically-related products – it is possible to undergo aspirin desensitization, causing tolerance to these medications to develop.

Perhaps most exciting of all, the BWH AERD program is conducting research into why some persons with asthma develop aspirin intolerance and exploring novel medical treatments that might help block it. More information is available at the BWH AERD website:

Saturday, November 24, 2012

The Controversy That Won’t Go Away

John Fauber, an investigative reporter, for the Milwaukee Journal Sentinel and the on-line publication MedPage Today, wrote an article published November 18 called “Advair: How Safe Is This Drug?”

In it he notes that Advair (and other similar medications, such as Symbicort and Dulera) contain two types of medications, an inhaled corticosteroid to suppress asthmatic inflammation and a long-acting beta-agonist bronchodilator to reverse or prevent constriction of bronchial muscles. He then references concerns about the safety of the long-acting beta-agonist bronchodilators, which “have been linked to 1,900 asthma deaths from 2004 through 2011, according to an estimate provided by AdverseEvents Inc.” He goes on to cite a separate analysis in 2008 by a researcher with the Food and Drug Administration, Dr. David Graham, that “estimated the drugs contributed to 14,000 asthma deaths from 1994 through 2007.”

Many physicians, like us, witnessed the dramatic improvement in the quality of life of persons with difficult asthma when the long-acting beta-agonist bronchodilators (salmeterol and later, formoterol) were first introduced in the 1990s. In Advair, two medications (salmeterol and fluticasone) delivered simultaneously from one device brought good asthma control to many who had struggled for years with frequent symptoms, asthmatic attacks, and complex inhaler regimens, sometimes including recommendations such as “take 4 puffs 4 times a day” of your triamcinolone inhaler (Azmacort). Remember that?

So how is it possible that these same highly effective medications are associated with an increased risk of death? Not cardiac deaths, but deaths from asthma attacks.

Here’s what we know:

•   Treatment with long-acting beta-agonist bronchodilators alone, without treating at the same time with an inhaled steroid such as fluticasone (Flovent), budesonide (Pulmicort), beclomethasone (Qvar), and others, is associated with more asthma attacks than treatment with an inhaled steroid alone.

•   Increased sales of the short-acting beta-agonist bronchodilator, isoproterenol, were associated with increased deaths among asthmatics in England in the 1960s; and increased sales of a different short-acting beta-agonist bronchodilator, fenoterol, were associated with increased deaths among asthmatics in Australia in the late 1970s. In neither instance were inhaled steroids combined with these beta-agonist bronchodilators.

•   In a large multi-center research study, when the long-acting beta-agonist bronchodilator, salmeterol, was compared to placebo among persons with asthma taking their “usual therapy,” whatever it might be, more people randomly assigned to receive salmeterol died from asthma attacks than those given placebo. Most of the persons in this study were not taking inhaled steroids.

Here's what we don't know:

•   Why are long-acting beta-agonist bronchodilators potentially harmful when used without concomitant anti-inflammatory therapy? Is it because persons with asthma come to rely on medications that relax bronchial smooth muscle and ignore the allergic swelling of the bronchial tubes and excess mucus production that can lead to fatal obstruction of the breathing passages, or is there some other mechanism?

•   If you use an inhaled steroid together with a long-acting beta-agonist bronchodilator, is the increased risk of a life-threatening attack eliminated? This question is currently being addressed by a series of long-term research studies comparing inhaled steroids alone versus inhaled steroids combined with long-acting beta-agonist bronchodilators. We will need to wait until 2017 to get the results of these investigations.

What do we conclude in the meantime?

We are struck by the fact that despite booming sales of Advair and similar medications over the past decade, asthma deaths in the United States have steadily declined. And we are reminded that the concern regarding the safety of long-acting beta-agonist bronchodilators relates to severe, fatal asthmatic attacks, not heart attacks, irregular heart rhythms, or mysterious sudden death. We believe that medications like Advair, combined with routine medical care, help to achieve good asthma control and protect against asthmatic attacks. If you are taking an inhaled steroid together with a long-acting beta-agonist bronchodilator, you and your doctor working together can ensure that you are safe from life-threatening asthmatic attacks.

P.S. Neither Dr. Sloane nor Dr. Fanta receives financial incentives of any sort from the pharmaceutical makers of Advair and related drugs.

Wednesday, September 19, 2012

A Farewell to Primatene® Mist (Almost)

In December, 2011, in accordance with its efforts to eliminate sale of CFC-containing inhalers because of the harmful effects of CFCs (chlorofluorocarbons) on the environment, the FDA banned the sale of Primatene® Mist, the over-the-counter (OTC) inhaled bronchodilator containing epinephrine. Suddenly, no low-cost bronchodilator could be purchased in the US without a prescription. The era of Primatene® Mist availability spanned 50 years, and it was estimated that as many as 2-3 million units were sold each year.

Is this a sad or happy farewell? Many would argue that its elimination is a good thing and long overdue. You may remember the headline stories from several years ago about Krissy Taylor, a young model, found dead clutching her Primatene® inhaler. She had self-treated asthma and died not from toxic effects of the medication but from inadequately treated asthma. It is a story that has likely been repeated many times, even if not always with such a tragic and fatal outcome: persons over-relying on bronchodilator therapy, self-treating their asthma without the guidance of a healthcare professional, developing worsening airflow obstruction due to inflammation of the airways (swelling and mucus plugging) while relying on a medication like Primatene® whose only effect is relaxation of the muscles surrounding the bronchial tubes. Making a bronchodilator available at relatively low cost without a prescription makes this scenario all the more possible.

There would be no debate about the benefits of eliminating sale of an OTC bronchodilator were prescription bronchodilators with ozone-friendly HFA (hydrofluoroalkane) propellants available in a low-cost, generic version (which they are not) and were primary care providers readily accessible to all asthma sufferers (which they are not), so that prescription medications could be quickly prescribed and obtained in the context of sound medical advice about asthma treatment. The idea that someone with asthma who is having difficulty breathing might not obtain relief because they cannot get the help of a medical provider and/or cannot afford the cost of a prescription bronchodilator is abhorrent to all. An important first step to solving this problem is once again marketing a generic albuterol (now albuterol-HFA). Inhaled albuterol likely is safer, more potent, with a longer duration of action than epinephrine.

While we engage in reasoned debate on this subject, a pharmaceutical company (Nephron) has found a commercially-driven solution: market a form of epinephrine (racemic epinephrine or racepinephrine) as a liquid delivered by a small hand-held atomizer device. It seems a step back into history, before the invention of metered-dose inhalers, when asthma medications like isoproterenol were delivered using a bulb atomizer. The product (AsthmaNephrin®) and the atomizer device (EZ Breathe®) are already in pharmacies across the country … and available without a prescription. For better or for worse, it appears that the marketplace has won out … again.

Saturday, August 18, 2012

Lessons Learned

The federal government’s Centers for Disease Control recently released statistics on the rates of current cigarette smoking among high-school students and adults in the United States.  The news was good: the percentage of high-school students (19.5%) and adults (19.3%) who are currently smoking cigarettes reached the lowest levels in 45 years. Given that in the U.S. cigarette smoking is the number one preventable cause of respiratory illness and death, this news is good for the health of the nation.

From the perspective of those with asthma, it is particularly encouraging. Cigarette smoking and second-hand cigarette smoke exposure are associated with worse symptoms of asthma. Cigarette smoking during pregnancy is thought linked to an increased risk that the newborn will develop asthma (and other respiratory illness). Cigarette smoking predisposes to respiratory tract infections that provoke asthmatic attacks. When parents stop smoking or smoke only outside of the home, children with asthma breathe better.

Why is it that fewer Americans are taking up cigarette smoking and more are quitting, despite billions of dollars spent by the manufacturers of cigarettes to encourage smoking? There is no single reason. In our opinion it is the combination of all anti-smoking efforts taken together that have successfully turned the tide. Each component of the anti-smoking campaign contributes: smoking bans in public places; cigarette taxes that drive up the cost; media campaigns vividly portraying the devastating consequences of emphysema, lung cancer, throat cancer, etc.; physician training in smoking cessation counseling; free community-based smoking cessation programs; and others. All together these efforts are slowly but steadily working to counter the powerful addictive allure of cigarette smoking.

We think that there is a lesson to be learned for treating and ultimately curing asthma. A single intervention that prevents its development or cures asthma in those living with the disease seems unlikely anytime soon. But multiple groups of scientists working together to understand the key processes involved in asthma; clinicians seeking better treatment strategies; pharmaceutical companies pursuing newer, safer medications; advocacy groups focusing attention on the importance of the disease; educators sharing information on the knowledge, skills, and attitudes needed to manage asthma effectively; local, state, and national asthma disease prevention and control programs working to create innovate programs, including promotion of healthier home and work environments; and patients and families helping other patients and families – these are some of the elements of a multi-pronged effort that will ultimately reduce asthma suffering and the risk of asthma attacks and death. Collaboration and sharing are key.

And the pay-off is not a remote pipedream. Already there is cause for encouragement. Although the number of persons in the U.S. with asthma remains high and is perhaps still on the rise, the number of persons hospitalized with asthma attacks or dying from asthma has been steadily decreasing for the last 10 years. Better care and better outcomes are realities within reach.

Saturday, July 21, 2012

Are Allergies Contributing to My Asthma?

Studies demonstrate that at least 60% of adults with asthma and 80% of children with asthma are sensitized to one or more common environmental allergens. But what is allergic sensitization, and how might being allergic to something contribute to asthma?

Allergies are the result of the immune system, a complex and diverse group of cells in the body, many of which start of in the bone marrow, then circulate in the blood as white blood cells, and eventually leave the blood to enter body tissues like the lungs and the gastrointestinal tract. It is believed that the immune system’s main function is to defend the body against danger. Most often, that danger is from infection – the invasion of the body by micro-organisms like bacteria, viruses, parasites, and fungi. The immune system is not only like a combined armed forces, police, and fire department (defending the healthy “citizens” of the body), but also a like a border guard, checking the identity of things that enter into the body every day when we breath, eat, and drink – weeding out the “terrorists” from the “tourists.”

Although a precise understanding of the molecular and cellular details is incomplete, a popular hypothesis is that allergies result when the immune system mistakenly identifies a harmless substance (such as dust mite or cat dander protein) as if it were dangerous. The immune response against these substances constitutes an allergic reaction. Among the many cells involved in such reactions, the mast cell is a powerful central player in allergies. Armed with claw-like molecules called “IgE antibodies,” mast cells in the airways can bind to allergenic proteins, which triggers the release of mast cell inflammatory chemicals like histamine, leukotrienes, and cytokines that bring about many of the features of asthma. Mast cell activation by allergens can lead to airway spasm (bronchoconstriction), mucus hypersecretion, and the influx of other inflammatory cells such as eosinophils. This allergic inflammation results in asthma symptoms like wheezing, cough, and breathlessness.

Allergies such as “hay fever” (known in medical parlance as “allergic rhinitis”) are common. Knowing whether allergies contribute to asthma can be an important part of prevention and treatment. If allergies are part of what drives your asthma, avoidance of allergic triggers, treatment with allergy medications, and the use of allergy immunotherapy (“allergy shots”) to reprogram the immune system away from its mistaken attack against common harmless substances may help. Allergy testing –blood testing or skin testing – in conjunction with a careful history and physical exam at a visit with an allergist can answer the question of whether or not allergies are contributing to your asthma.

Saturday, July 14, 2012

Long-Acting Beta Agonists (LABAs) - Why All the Fuss?

Every package insert of a medication containing salmeterol (Serevent) or formoterol (Foradil), including the very popular and effective bronchodilator-steroid combinations, Advair, Symbicort, and Dulera, includes a black-box warning about serious potential risks from these long-acting beta-agonist bronchodilators. In persons with asthma, the warning notes, use of these medications is associated with an increased risk of death and near-death (requiring ICU care) from an asthma attack.

Therein lies a major dilemma. Highly effective medications used to control asthma, recommended by national and international panels of experts in their Guidelines for optimal management of asthma, may pose a risk of causing a fatal or near-fatal asthma attack. Why do we say “may” pose a risk? Evidence from a large study (26,000 subjects) indicated an increase in asthma deaths and near-fatal asthma attacks among persons treated with salmeterol compared to placebo, but it did not control what other medications persons participating in this study were taking. Most of the subjects were not taking an inhaled steroid. It is well accepted that a long-acting beta agonist without a medication to control the inflammation of the bronchial tubes in asthma is a bad idea. But what about patients who take an inhaled steroid (such as those combined with a long-acting bronchodilator in Advair, Symbicort, and Dulera)? Are they then safe from any increased risk of severe asthma attacks?

This question is central to the future of asthma care. The answer is too important to leave to speculation and opinion. So the FDA has mandated that a large-scale study be performed in which all subjects (more than 45,000 to be recruited) will receive an inhaled steroid. In addition, half will also receive a long-acting beta-agonist bronchodilator and half will receive a placebo. Participants will be observed for 6 months to determine whether the two groups have any differences in their rates of hospitalization, respiratory failure, or death from asthma. And then – around 2017 – we will know the answer.

In the meantime, we rely on hunch, intuition, and best guess based on information currently available. Our bias is that the long-acting beta-agonist bronchodilators when used in combination with an inhaled steroid will prove to be safe as well as effective.

P.S. Long-acting beta-agonists in patients with COPD are not associated with any increase in respiratory-related deaths or near-deaths from COPD.

Saturday, June 9, 2012

Going Generic

Montelukast (Singulair) is the most widely prescribed leukotriene blocker in the United States. It is used to treat both asthma and allergic rhinitis and is approved for both very young children and for adults. It has been a mainstay of asthma and allergy treatment since first approved by the Food and Drug Administration (FDA) in 1998 … and it is costly! On average, a one-month supply costs approximately $150 or as much as $5 per tablet.  Financial relief may be on the way. The US patent for Singulair expires in August of this year, and it is very possible that a generic version of montelukast will be made available soon thereafter.

In general, manufacturers of generic medications are able to sell their medications at a lower cost than the original brand-name version.  The FDA is charged with ensuring that the generic medications are equally effective and safe as their brand-name predecessors.  This past year has seen approval of generic atorvastatin (Lipitor), the cholesterol-lowering medication, and of levofloxacin (Levaquin), a powerful antibiotic. Now, a low-cost generic montelukast may be on its way.

What's our opinion about generics?  In general, we are big fans.  We perceive them as an important way to reduce medication costs, make medications more widely available to those who need them (because of increased affordability), and help reduce the inflated cost of healthcare in America.  True, one may occasionally find that a brand-name version of a medication works better for you or is better tolerated, but that tends to be the exception rather than the rule.  Many, many people miss generic albuterol by metered-dose inhaler, having come to accept the generic version -- when it was still available -- as every bit as good as the branded albuterol inhalers (ProAir, Proventil, and Ventolin). 

On our wishlist: a generic and lower cost inhaled steroid by metered-dose inhaler (such as a generic fluticasone or beclomethasone).  By making inhaled steroids more affordable and thereby more widely used, it would save lives and reduce asthma hospitalizations and emergency department visits across the country.