One Inhaler or Two?

In the U.S. most persons with more than occasional symptoms of asthma have two inhalers: one taken regularly to suppress airway inflammation and prevent asthmatic attacks, the other to be used “as needed” when symptoms of asthma flare.  One is the “controller,” the other the “quick-reliever.”  In most instances, the controller inhaler provides no immediate relief of asthma symptoms, and the quick–reliever inhaler provides no long-term benefit to quiet the inflamed airways. 
One can quickly see the potential for confusion.  “Which inhaler did the doctor say I should take every day, which one only when I was short of breath or wheezing?”  The two inhalers may look virtually identical, except for color.  For other people, the complexity relates to two different types of inhalers.  In the U.S. all of our quick-relievers come in the form of metered-dose inhalers – a metal canister in a plastic holder from which a short “puff” of medication is released.  However, the controller inhalers may take the form of dry-powder inhalers, which require a forceful inhalation to pull the powdered medication from its canister.  Then there is the issue of frequency of use: most controller inhalers are meant to be taken once or twice a day and no more; the quick-reliever can be used up to four times a day and even more often in an acute crisis.

What if ….?  What if there were one inhaler that could be used both as a controller and as a quick-reliever, for maintenance and for rescue?  One device, one technique to be mastered in order to inhale the medication optimally.  Use it once or twice to a day to keep your asthma quiet, use extra doses from the same inhaler if you find yourself short of breath or wheezing.  Such an inhaler, containing a combination of two medications, is available … although in the U.S. it is not recommended for use in this way … yet.

What made this single inhaler for both maintenance and rescue possible was the development of a bronchodilator that both exerts its effect quickly (within 3-5 minutes) and also maintains its effect all day (or night) long.  This medication is the long-acting bronchodilator, formoterol, which works for at least 12 hours to hold open the bronchial tubes, but with an additional dose acts as a quick-reliever.  It is combined with an inhaled steroid in the two inhalers, Symbicort and Dulera.  Symbicort combines formoterol with the anti-inflammatory steroid, budesonide; Dulera combines formoterol with the anti-inflammatory steroid, mometasone. 

Taken every day, these combination steroid/long-acting bronchodilator inhalers can keep asthma under good control.  If asthma flares up, additional doses provide quick relief and at the same time escalate the amount of controller medication, until asthma again quiets.  A recent study published in Lancet Respiratory Medicine confirmed prior reports that this approach is effective and, in the long run, may help to keep the dose of inhaled steroids as low as possible, which is a good thing.

So why have U.S. physicians not embraced this approach?  First and foremost is the lingering concern, previously discussed in this blog (see "The Contoversy That Won't Go Away"), that in some patients long-acting bronchodilators like formoterol may on rare occasion lessen asthma control and cause severe, even fatal asthma attacks.  Although some would argue that the long-acting bronchodilators are potentially dangerous only when used without an accompanying inhaled steroid, definitive research to test this hypothesis is currently being conducted and the results are years away.  Other concerns relate to potential side effects from overuse of a long-acting bronchodilator: if jitteriness or heart racing develops, the side effect will likely last for many hours. 

We do not anticipate that practice will change in the U.S. any time soon.   For now, we are committed to two separate inhalers: one used regularly for control of asthma; one taken as needed for quick relief of troublesome symptoms.  But depending on the results of current research into the long-term safety of long-acting bronchodilators when combined with an inhaled steroid, a small revolution in asthma care may be coming down the road.

Should I Worry About Taking Azithromycin?

Azithromycin is one of the most widely used antibiotics in the United States.  In 2011 more than 40 million Americans received a prescription for azithromycin (Zithromax; Z-pak; Zmax).  Recently, the Food and Drug Administration distributed a drug safety announcement regarding the risk of azithromycin in causing fatal heart arrhythmias (irregular heart beat).  Should we now stop using azithromycin?

Here's how this drug safety warning came about.  Last year researchers reviewed the electronic records of Medicaid patients in Tennessee.  They found that persons receiving a short course of azithromycin were more likely to suffer death from cardiovascular disease, especially sudden death thought due to heart arrhythmia, than persons not receiving antibiotics or receiving an alternative antibiotic, amoxicillin.  If you were a person with no special risk for cardiovascular disease, then the increased risk of dying while taking azithromycin was approximately 1 in 111,000.  If you had serious underlying cardiovascular disease or a tendency to develop heart irregularity, the excess risk of dying while taking azithromycin was 1 in 4,000.  To put this in perspective, your risk of dying from a bolt of lightning is estimated at 1 in 84,000, and your risk of dying in an automobile accident is estimated at 1 in 100.

There are two classes of antibiotics that are known to predispose to irregular heart rhythms.  These are the family of antibiotics called macrolides (including azithromycin, clarithromycin [Biaxin], and erythromycin) and fluoroquinolones (including ciprofloxacin [Cipro], levofloxacin [Levaquin], and moxifloxacin [Avelox]).  The study cited above found that the risk of cardiovascular death when taking levofloxacin was the same as when taking azithromycin.  It also found that the risk of death from cardiovascular disease did not persist after the course of antibiotic.

Our take on this evidence? 

1.   The evidence suggesting that azithromycin can stimulate fatal heart arrhythmias is compelling and believable. 

2.      Will we continue to prescribe azithromycin for our otherwise healthy patients and family members for bacterial respiratory tract infections?  Yes.  Antibiotics remain among the relatively few drugs in our medical toolbox that can cure disease.

 

3.      People who should avoid azithromycin (and other macrolide antibiotics) and levofloxacin (and other fluoroquinolone antibiotics) are those with a known tendency to a particular type of irregular heart rhythm of the ventricle (ventricular arrhythmia) caused by slow electrical repolarization of the heart muscle, manifesting as prolongation of the QT interval on electrocardiogram.  Your doctor will know if you have “prolonged QT syndrome” or are taking other medications that might cause a prolonged QT interval, especially heart medicines such as dofetilide, amiodarone, or sotalol.  A very low blood level of potassium or an abnormally slow heart rate might also put you at risk for this type of heart arrhythmia.

4.      Is this evidence one more reason that otherwise healthy people with viral head and chest colds should take symptomatic treatment (such as acetaminophen [Tylenol], chicken soup, and tea with honey) rather than unnecessary and unhelpful antibiotics?  Definitely yes.

Asthma and Your Bone Health

Asthma is a disease of the lungs, not the bones. There are no bones in our bronchial tubes, right? So where is the connection?


The most important connection relates to the anti-inflammatory steroids ("corticosteroids") used to treat asthma. Prednisone and methylprednisolone (Medrol), if taken regularly or for many months of the year, can have major effects on the bones. In children they can impair bone growth, leading to lesser height as an adult. In adults steroids can decrease bone mass and predispose to the thinning of the bones called osteoporosis. Osteoporosis is a condition without symptoms but one that predisposes to fractures, sometimes with minimal or no trauma. Osteoporosis can cause vertebrae to collapse in on themselves (vertebral compression fractures), ribs to break with coughing or twisting, and hips to break when we fall.

Because of these and many other negative effects of corticosteroids taken as tablets (and distributed via the bloodstream to all parts of the body), safer alternatives to treat the inflamed airways of asthma were developed. In the 1960s corticosteroids that could be delivered directly to the bronchial tubes in the form of medication aerosols became available. The first widely used formulation was beclomethasone by metered-dose inhaler. Since then other corticosteroid preparations have become available, some as metered-dose inhalers, some as dry-powder inhalers, and one as a solution for nebulization. These medications are given in a small fraction of the dose of oral steroid tablets, and only a small portion of the inhaled medication makes its way into the bloodstream, to be carried to the bones and elsewhere throughout the body. As a result inhaled steroids are far safer for the bones than oral steroids.

And yet. A small portion of the inhaled steroid can be absorbed into the blood and carried to the bones. If the dose of inhaled steroid is high enough and the duration of use long enough, it is possible that over a period of several years steroids by inhalation, like steroids swallowed as tablets, can have some effect on bone health. And for many people, it is not an either-or proposition. Many people require daily inhaled steroids for control of asthma plus occasional bursts of oral steroids to reverse flare-ups or asthma attacks.

The potential risk to your bones from long-term use of high doses of inhaled steroids does not mean that you should stop using your steroid inhaler. In most instances, inhaled steroids prevent or reduce the need for oral steroid tablets, which have a far greater impact on your bones. Rather, it means that we -- patients and healthcare providers alike -- need to be vigilant about maintaining good bone health. Regular weight-bearing physical activity is a good place to start to strengthen our bones. Adequate intake of calcium and vitamin D, either in our diets or as dietary supplements, is important "fuel" for our bones. Also, several prescription medicines are available that can slow the development of osteoporosis and even reverse it.

Your healthcare provider can help you assess your risk for low bone mass. He or she may recommend measurement of your bone density with an X-ray specifically designed for this purpose, called bone densitometry or a "DEXA" scan (dual-energy X-ray absorptiometry scan). Persons at risk for osteoporosis (especially -- but not only -- thin women following menopause) are typically screened with bone density X-rays approximately every two years. Remember: good breathing and good bone health are both achievable.

Can Asthma Turn into Emphysema?

For the most part, asthma and emphysema are two distinct and unrelated diseases. Asthma most often begins in childhood and is closely related to allergies. Emphysema begins in middle age or later and is almost always due to cigarette smoking. Asthma is a disorder of the bronchial tubes, with difficult breathing resulting from swelling of the air tubes and contraction or “spasm” of the muscles that surround those tubes (“bronchospasm”). Emphysema involves destruction of the walls of the air sacs deep in the lungs (the “alveoli”), and as a result, loss of elasticity of the lungs. In emphysema air easily enters the lungs when we breathe in, but slowly empties from the lungs when we breathe out because the springiness or elasticity of the lungs has been lost, like an old rubber band that has lost its recoil.


And the biggest difference between asthma and emphysema is that persons with asthma who are free of symptoms are expected to have normal or near-normal lung function (their bronchial tube inflammation has abated and their bronchial muscles are not in spasm). Persons with emphysema have permanent loss of lung function; even on a good day, the lung damage remains and breathing capacity is impaired.

But … and there always seems to be a “but” when making general assertions about biology … not everyone with asthma, when well, achieves normal or near-normal lung function. Perhaps you are one of those people with asthma who never smoked cigarettes, have no reason to have emphysema, and yet even under the best of circumstances and with maximal asthma treatment still have reduced lung function. You get short of breath more easily than other people when you exert yourself, and tests of your lung function remain far from normal, even when you are doing well. You have a component of permanent, irreversible narrowing of your bronchial tubes. Doctors sometimes call it “fixed” airways narrowing, in the sense of “stuck” or “immovable.” Although you do not have emphysema (destruction of the walls of the air sacs in your lungs), you have a similar problem: a permanent reduction in your breathing capacity.

It is not difficult to envision that some people with asthma might develop scarring in and around their bronchial tubes, and scar formation lasts forever. All the rest seems to be unknown, however: why do some people with asthma develop this permanent airway narrowing and most others not; when does it happen in the lifelong course of asthma; is it always progressive; and is there any way to prevent it? We know that in persons with asthma, permanent airway narrowing is associated with cigarette smoking; and we shouldn’t smoke. What else? Childhood illness resulting in impaired lung growth? Long-term asthma that has been inadequately treated? Recurrent asthmatic exacerbations that cause a “step-wise” decline in lung capacity?  These are all potential explanations, but none is certain; and different people may be affected by different mechanisms.

No, asthma does not turn into emphysema. But, yes, in some persons asthma can result in permanent narrowing of the breathing tubes that might, strictly speaking, be considered a “chronic obstructive pulmonary disease” or COPD. A “holy grail” of asthma research is discovery of the causes of this scarring of the bronchial tubes and its prevention. We are at the very beginning of a long road to discovery and cure.

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: http://aerd.partners.org.

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.

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.