Thursday, December 11, 2008

Long Acting Beta Agonist Inhalers 'CAUSE' Asthma? The DMCB Explains and Reviews the Implications for Disease Management

A Food and Drug Administration (FDA) expert panel has recommended that the ‘long acting beta agonist inhalers Foradil and Serevent no longer be approved for treatment of asthma. Apparently they can cause asthma. Drugs that treat asthma can cause asthma? How can this be true? And what are the implications for disease management?

The Disease Management Care Blog at your service!

First of all, “beta agonists” are a type of drug that works by activating “beta receptors.” Receptors are a type of protein that sits on the external surfaces of cells. There are many different types of receptors that stick out from the surfaces of individual cells in the human body, each of which has a different function and each of which lead to a cascade of chemical signals on the inside of the cell. This in turn leads to changes in cell function. The DMCB thinks these receptors were named “beta” because they were the second type of receptor that scientists discovered after they found the ‘alpha receptors.’

Think of this as a lock (the receptor) and a key (the agonist*). The human body uses these receptor-‘locks’ to orchestrate responses to changes in the external environment. For example, epinephrine is one of many agonist-‘keys’ that are transported via the bloodstream throughout the body. A boost in epinephrine levels causes stimulation of beta receptors in the body, which prompts cells to act. In the case of the muscle cells that line the airways of the lung, the cells relax, which causes the airways to dilate. That makes sense, because if you are in a situation that is physically stressful, you want your lungs to be wide open.

The problem? Scientists have known for decades that when beta receptors are stimulated repeatedly and excessively, human cells ‘uncouple’ them from the cells’ internal machinery and remove them from the surface of the cell. There are beta receptors in the heart, for example, and repeated doses of epinephrine-like drugs over days of treatment become less effective. Among persons with asthma, the impact of epinephrine inhalers can also decrease. In other words, beta agonist drugs work great at first, but with time, they can become less and less effective. This loss of effectiveness is far more likely to occur if large and repeated doses are used over many days.

Asthma is a condition in which inflammation of the air passages causes the muscles that surrounds those air passages to go into spasm. Inhaled beta agonist drug mists cause those muscles to relax. The good news is that small, judicious doses of beta agonists do not cause loss of effectiveness. The bad news is that asthma is a variable disease and beta agonists may not be enough for a bad attack. There is a temptation among doctors and patients to increase doses of the beta agonist drug when symptoms are getting worse, which leads to poor receptors which can lead to a paradoxical loss of effectiveness.

Check out this report from the New England Journal of Medicine from as far back as 1992 that showed that beta agonists were associated with increased asthma death rates. In this instance, there were over 12,000 asthma patients and 129 died from an asthma related death. The odds were very small, but death seemed to be associated with the ‘regular’ use of the beta agonist. Think of it this way: beta agonist treatment leads to improvement in most persons with asthma, but a small fraction of persons will be exposed to excessive doses, leading to loss of disease control and death.

What about ‘long acting’ beta agonists? These drugs were just recently invented and are chemically formulated to resist metabolism, which means they stick around longer. That means patients don't need to use them as often, which is good. Recall that repeated stimulation of beta receptors can cause dwindling of effectiveness, so long acting beta agonists could theoretically be worse than their shorter acting and older cousins. Research scientists were looking for that side effect in this study and found that there was a small increase in deaths. There were about 10 excess deaths among more than 26,000 patients.

The FDA says that there are clinical trials that show that if you are going to use a long acting beta agonist inhaler, it should be paired with a drug that reduces inflammation. By reducing the inflammation, the airways are more likely to respond to the agonist which reduces the chance of repeated dosing and the paradoxical loss of effectiveness. The opposite may be true also: use of the long acting beta agonist drug may permit the use a lower dose of the anti-inflammatory drug. These are steroids, which may have their own problems including osteoporosis and eye problems such as cataracts and glaucoma.

What does the DMCB think about all this?

1. The mechanism behind the paradoxical loss of effectiveness from over-stimulation of beta receptors have been known about for a long time. Smaller judicious doses are safe.

2. While the excess death rate from long acting beta agonists is small, it’s real and it’s been known about for a long time. Adding an anti-inflammatory medicine makes sense. Using both medications makes the risk of each lower.

3. The DMCB suspects asthma disease management organizations were already managing this risk during the course of their coaching and patient education. That was true in the DMCB’s former life when it was helping to run a disease management organization. Too bad there don’t appear to be any publications about it (do any readers know otherwise?)

4. If you are working for a disease management organization while you are reading this the day after the FDA announcement, ask yourself if your company is currently telephoning all the persons on just a long acting beta agonist inhaler to help them switch one that also contains an anti-inflammatory component. If not, maybe you should be.

5. If you are working in a medical home and have an electronic medical record that lists everyone’s diagnosis and medications, ask yourself if your clinic is currently telephoning all the persons on just a long acting beta agonist inhaler to help them switch to one that contains an anti-inflammatory component. If not, maybe you should be.

* as an aside, there are drugs that can block receptors, causing them to be inactivated. These dummy keys are called 'antagonists.' Now you know how beta blockers got their name.


Anonymous said...

maybe medicares electronic prescribing mandate is indeed a good idea!

Jaan Sidorov said...

Maybe you're right. If the insurers and pharmacy benefit managers are unable to demonstrate that they can use their data bases to deliver even greater value to the consumer, the Feds will either take it over or create to mandates and regulations.