Thursday, February 18, 2010

FDA Blows it on LABA Safety

The FDA just killed a few asthmatics!

I have blogged extensively regarding LABA safety (see The Lowdown on LABA's , Good News for Asthma Patients , Asthma Medication: Calling Out the Safey Advocates and Dear FDA, Remove the Boxed Warning from Advair and Symbicort )

As reported today in the Wall Street Journal and MSNBC (so far), the FDA announced today that is was changing the labelling on products containing long acting beta2 agonists, or LABA's. One of the changes was recommending that "LABAs should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved."

Not only did the FDA get it wrong regarding their interpretation of the data, but they did two surprising things. First, in addition to simply saying what is safe and what is not (their job), they made treatment recommendations (not their job); recommedations that are actually not consistent with national guidelines. Secondly, their recommendations are based on absolutely no data! In fact, the limited data available would suggest that their approach may not be a good idea. Finally, taken together with the fact some of the headlines will scare patients and cause them to simply stop taking their medications, patient will undoubtedbly suffer. Ironically, the FDA's reaction to the few potential harmful effects that they are worried about regarding LABA's have led to actions that will likely cause substantially more harm to patients.


At face value, the LABA safety issue should not be an issue. Asthma deaths climbed steadily into the mid 90's, unlit about 1996/1997 when the rate of asthma deaths declined for the next decade and have remained stable over the past few years at about 4000 death per year. LABA's were introduced at exactly the time that asthma deaths declined. Though one can not prove that the decline in asthma death rates are due to the use of LABA's, it certainly can not be the case that LABA's cause asthma deaths.

One of the FDA"s recommendations did make sense: LABA's should not be taken alone and only used with an inhaled corticosteroid or ICS. The entire LABA controversy centers around the SMART study published back in 2006. SMART was a very large (over 23,00 patients) study done by GSK, the makers of the LABA salmeterol, looking at its safety. The problem was that it didn't study only asthmatics taking ICS, but asthmatics taking any medication. The study was stopped early because certain subsets of patients, particularly African Americans, seemed to have increased risk, including asthma death. Because of these findings, the FDA not only applied a boxed warning to salmeterol, but all LABAs and products containing LABAs. Advair, one of the most common asthma controller medications contains the LABA salmeterol and an ICS. The data from the SMART study was very clear that most of the problems came from asthmatics taking LABA's alone, and that there were no increased problems (regardless of ethnicity) when using a LABA with and ICS. In fact, no one taking Advair or Symbicort equivalents in the SMART study died! However, this was not enough for the FDA or critics to give ICS plus LABA products a pass on the boxed warning. The only way to prove to the FDA (and some critics) that ICS + LABA's are safe would be to do another SMART like trial on patients taking ICS alone or ICS+LABA. The problem is that this trial would likely require at least 250,000 patients (because events are so rare), and no drug company is going to fund that study. In an effort to get more data, several meta-analysis were done. GSK's own meta-analysis which looked at ICS + salmeterol compared to ICS alone showed that ICS + LABA actually decreases the risk for severe exacerbations, and did not increase the risk for asthma-related hospitalizations or asthma-related deaths. The FDA did their own meta-analysis (most of the data coming from SMART) which seemed to show the same thing. In fact, regarding Advair, the committee voted 27 to 0 that Advair was safe. Thus, it is quite surprising that the FDA would go in a different direction that what their advisor committee was suggesting.


The most recent asthma guidelines were published in November 2007. There is a strong focus on asthma control. The guidelines say that the focus of asthma care should be control, and that if control is not achieved, therapy must be stepped up, because poorly controlled asthma puts patients at risk for bad outcomes, such as hospitalization and death. In a recent study, we showed that that majority of patients in the primary care setting had poorly controlled asthma, and that one out of every three patients seen in primary care was using a rescue albuterol inhaler every day. The guidelines suggest that once asthma control is achieved that providers can continue therapy or CONSIDER stepping down. The guidelines are very specific that step down therapy should be done carefully, as it might risk worsening asthma. In addition, when talking about step down therapy, most of the discussion in the guidelines is about reducing the dose of the ICS, and not discontinuing the LABA (supported by data published in the New England Journal) Thus, by mandating that patients who are well controlled on ICS+LABA step down to an ICS alone, the FDA is both dictating treatment, which is not really their role, and in doing so, going against well accepted guidelines developed by an expert panel from the NIH! More importantly, there is extremely limited data on which route is best in a stable asthmatic patient: continuing ICS + LABA or stepping down to ICS alone. One study in the US of 647 patients controlled on Advair did worse when stepped down to ICS alone. Another French study of 467 asthmatics studied over 6 months showed that stepping down to a lower dose of Advair was fine, but stepping down to ICS alone (what the FDA recommends) caused problems. There are only a couple more studies like this done, all showing the same thing: the FDA's recommendations are ill advised.


There is very compelling data that shows when asthmatics stop their controller medications, that bad things happen, including ER visits, hospitalizations, and even death. First, though data is limited, there are studies which suggest that patients taking ICS + LABA are more likely to refill their prescriptions than those taking ICS inhalers alone. In fact, in one managed care study, the adherence to ICS + LABA in one inhaler (i.e Advair) was double that of patients taking the ICS alone. In addition, prescriptions for the rescue medication albuterol, as sign of worsening asthma, was higher in those patients taking an ICS alone. Thus, it is possible that patients who step down from and ICS + LABA to an ICS alone may not be as adherent to their controller asthma medication, and could get sicker. Finally, many physicians will attest to the fact that when there is bad press about a medicine, patients will stop, sometimes without discussing it with their doctor. We looked at patients in our practice after the Avandia scare in 2007, and found that many stopped taking the medication without discussing this with one of our physicians. Anecdotally, when the SMART data was first released and drew media attention, several physicians from various parts of the country told me they noticed increased ER visits due to asthma. This is why I am certain that the FDA decision today will cause patient harm.


james gaulte said...

Excellent commentary. The ghost of SMART continues to haunt patients and physicians.

The SMART trial should be studied as a text book example of how not to do a clinical trial.I had hoped that the 2006 review by Ernst et al published in the Annals of Internal Medicine and several other publications that exonerated LABAs ( as long as they are used with ICS) would have purged the dangerous notions brought by SMART and the subsequent Annals meta-analysis done by the Salpeter duo. However, for reason(s) that escape me now the FDA "revisits" the issue and issues dicta that in my opinion are not supported by good data and which are very likely to cause harm as you point out in your

Anonymous said...

I find your take on this topic interesting and well considered, however would like your thoughts on the following:

The SMART study was intended to provide information about LABA safety. What seems to be overlooked, however, is that asthma is a disease demanding supervision, yet the study paid little attention was paid to the care that the subjects actually received, even those who died.

The patients were recruited from the media, and not from physicians or clinics. Intake was one visit. Patients were given a half-year's worth of study medication, and instructed to maintain their own medicines and asthma care, whatever it was. They were contacted five more times, once a month, and only by phone.

There is virtually no other reported detail on the care given to these patients. "Compliance with study medication or concurrent asthma medication was not reinforced during study contact."

If I were charged with evaluating LABA safety (say, the FDA), the first thing I would ask for would be about the care received by subjects who died. Were they supervised… at all? Did they see a caregiver? Was care mostly in the ER? Did they fill their other medication? Did they rely on free study medication and nothing else? Was appropriate rescue medicine available (albuteral was provided if subjects did not have it, but for how long and what were the needs)?

Without this information, how is one to come to a conclusion? Rather than telling us much about LABA safety, it may be that the SMART study is simply a reminder of what can happen if the element of “taking care of the patient” is forgotten, or ignored.

jay said...

LABA Serevent was found to cause deaths. But why does the FDA have warning on other LABAs such as Formoterol. Have there been data to suggest that they cause death too ?

Dr. Matthew Mintz said...

FDA considers this a class effect. Given the fact that deaths were likely causes by LABA use without ICS use, it probably applies to Formoterol as well.

HOLLY said...

Thank you for this blog info. I am a nurse practitioner with mod persist asthma and have tried to step down slowly to my own detriment. Not only do i know how my patients feel but I understand how stepping down could potentially cause huge adverse outcomes. I appreciate you putting the info down plain also so i may refer patients to understand why I order and practice as I do.
Thanks again!

HOLLY said...

Thank you for this blog info. I am a nurse practitioner with mod persist asthma and have tried to step down slowly to my own detriment. Not only do i know how my patients feel but I understand how stepping down could potentially cause huge adverse outcomes. I appreciate you putting the info down plain also so i may refer patients to understand why I order and practice as I do.
Thanks again!