Back in February, I blogged about the FDA's recommendations regarding long acting beta agonist (LABA) safety (see FDA Blows it on LABA Safety ). A few weeks ago the FDA finalized these recommendations. Though some make sense, such as not taking a LABA without an inhaled corticosteroid (ICS), the main one I have a problem with is the following recommendation for patients controlled on an ICS/LABA combo like Advair or Symbicort:
"Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid."
Though the language is a little better than the original version which stated 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," The notion that stepping down the LABA is preferred to stepping down the dose of the ICS is not evidence based.
As mentioned previously, all the controversy come from the SMART study published back in 2006 which looked at the safety of salmeterol. The study was stopped early because certain subsets of patients, particularly African Americans, seemed to have increased risk, including asthma death. However, the data from the SMART study was very clear that most of the problems came from asthmatics taking LABA's alone. More importantly, there were no increased problems (regardless of ethnicity) when using a LABA with and ICS. The ICS seems to protect against rare, but serious problems associated with LABAs. In fact, no one taking Advair or Symbicort equivalents in the SMART study died.
The FDA, acknowledging that some patients need ICS/LABA's to control their asthma, but concerned about any potential LABA safety issue, recommend step down care for those on combination therapy that are now controlled. Interestingly, the NIH guidelines when discussing step down therapy not only mention that it should be done carefully, as it might risk worsening asthma, but also focus on reducing the dose of the ICS, and not discontinuing the LABA.
The fact the FDA (whose job it should be to tell whether or not a drug is safe or effective) has clinical recommendations that seem to contradict the NIH (whose job it is to make clinical recommendations) is enough to cause concern. However, even more startling is that fact that the data shows that the FDA is clearly wrong. As mentioned in my previous post,
one study in the US of 647 patients controlled on Advair did worse when stepped down to ICS alone, and 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. Today, a new study was just published confirming the same thing: stepping down the LABA is ill advised in a well controlled asthmatic. The study, published ahead of print online, looked at two large managed care databases over several years. They found 4350 asthmatics who stepped down from Advair: 3881 stepped down to a lower dose of Advair and 469 stepped down to the ICS alone (what the FDA recommends). When they matched the patients for age, demographics, etc. they found that the asthmatics stepping down to the lower dose of Advair had 30% fewer prescriptions for short-acting beta-agonists, a 26% lower risk of receiving systemic corticosteroids, and a 48% lower risk of asthma-related hospitalization or Emergency Department visit during follow-up.
Don't take my word for it
If you still remain skeptical, don't take my word for it. Look elsewhere. In Canada, where they have access to the exact same data, the label for Advair is completely different. You can access the full label by clicking here. However, the following excerpt says it all:
"Patients should be regularly reassessed so that the strength of ADVAIR® they are receiving remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose of fluticasone propionate at which effective control of symptoms is maintained."
In other words, the Canadian Advair label is consistent with what the evidence shows, and consistent with what our own NIH guidelines recommend. The FDA's versions is the opposite.
In the UK, the safety information not only has no mention of stepping down, but their is also no "black box" warning or even mention of the SMART study. The Brits only mention SMART when discussing Severent.
Bottom Line: The LABA safety issue is more about politics then science. LABA's should not be taken alone, but in combination with and ICS (like Advair and Symbicort) are the most effective agents for asthma and are completely safe. The goal for any physician is to have the patient on the lowest amount of medication possible to keep their condition under control. For asthmatics well controlled on ICS/LABA, the data is crystal clear. Despite what the FDA says, it is better to go to a lower dose ICS and remain on an ICS/LABA combo, then to go off the LABA and remain on the ICS alone.