Sunday, December 7, 2008

The Lowdown on LABA's

There has been some recent media coverage ( NY times, AP) on the safety of LABA's (long acting beta 2 agonists) which are used to treat both asthma and COPD. This stems from a recent release of data from the FDA (here is the 6.5MB 460 page document-download if you dare) in preparation for and advisory committee this Tuesday and Wednesday regarding the safety of LABA's. The meta-analysis released on 12/5 generated some additional safety concerns. GSK and Astra Zeneca (makers of Advair and Symbicort respectively, products that both contain LABA's) have already issued press releases. The results of the advisory committee meeting this week could range from pulling all LABA products from the market to keeping the on the market with even less cautionary warnings due to safety reassurances.

To prepare you for what is likely to be a major showdown this week between Big Pharma, the FDA, clinicians, consumer rights activitists and patient advocates on this critically important and controversial topic, I am providing you with the "Lowdown on LABA's."

The Role of LABA's
Inhaled corticosteroids (ICS) have been one of most significant advances in the treatment of asthma. Prior to this, asthmatics used short acting beta 2 agonists (SABA's) to relieve their symptoms, but this did not treat the underlying disease caused by inflammation. ICS's are anti-inflammatory and have been shown to improve symptoms, reduce the need for hospitalization and even save lives. For this reason the 2007 NIH asthma guidelines recommends ICS as first line therapy for all asthmatics. However, sometime ICS are not enough. LABA's were introduced in the late 90's and had substantial impact. Unlike SABA's which last only a few hours and are intended to take as needed, LABA's last 12 hours and were intended to be taken on a regular basis. Interestingly, though LABA's are indicated for the treatment of asthma, the NIH and WHO guidelines never intended LABA's to be used without an ICS, but rather used in combination. It should be no surprise that Advair, a combination of ICS plus LABA, became one of the world's most popular prescription drugs and the number one maintanence inhaler for asthma. Since other asthma drugs existed (theophyline, chromolyn sodium) or were recent to the market (Singulair), there was some question in the late 90's as to which was the next medication to add after ICS. In 2002, the NIH answered this question, stating that after ICS, adding a LABA was the next best choice. It was better than doubling the dose of ICS, better than adding Singulair, etc. The NIH stated that the evidence was clear: if ICS alone doesn't work, add a LABA.

The SMART study
I have blogged about the SMART study several times. In response to The truth on the 8 drugs doctors wouldn't take and regarding Good News for Asthma Patients. Basically, due to possible safety concerns due to salmeterol (LABA used in Advair), GSK conducted a very large (over 23,00 patients) study safety study. 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 death. Though there have been criticisms of the study, the FDA applied a boxed warning not only to salmeterol, but all LABAs and products containing LABAs. In the analysis it was clear that most of the problems came from taking LABA's alone, and that there was no increased problem (regardless of ethnicity) when using a LABA with and ICS (no one taking Advair or Symbicort equivalents in the study died). However, this was not enough for the FDA or critics to give ICS plus LABA products a pass on the boxed warning. Several other papers came out regarding this. Salpeter's meta-analysis received a lot of attention (cited in the popluar men's health article and had Katie Couric repeating that "4 of 5 asthma deaths were due to Advair). However, the meta-analysis was flawed because all of the death data was based on the SMART study, and like the SMART study some patients were taking ICS and some were not. In addition, if anything, since the introduction of LABA's the asthma death rate has gone down, not up, suggesting that LABA's may be one of the reasons asthma death has decreased to an all time low. A recent meta-analysis showed that when LABA's are used (as they always should have been) with an ICS, there were no increased exacerbations and deaths, and as in the previous studies, patients did better. Regardless, SMART could not be put to rest and the 2007 NIH guidelines backed down from the 2002 preference of ICS +LABA, suggesting doctors weigh the risks and benefits of ICS + LABA vs. increasing the ICS dose. In addition, the FDA decided it would revisit the issue, and thus the meeting this week is now being held.

The FDA Data
The agenda and other material can be found here, here and here. Several of the advisory committees basically plan to review all of the data and make recommendations to the FDA for a final decision.

In preparation for this big meeting, the FDA did it's own meta-analysis of 110 trials of two LABA's -formoterol (Foradil) and salmeterol (Serevent)- and the two ICS/LABA combinations - salmeterol/fluticasone (Advair), and formoterol/budesonide (Symbicort)-available in the US; however, most of the data come from salmeterol (Severent/Advair) studies. They looked at over 60,000 patients, of which the SMART study accounted for over 40%. They found an increased risk of hospitalization and asthma related death for patients on LABA's, particularly in children ages 4 to 11, with a risk difference estimate of 14.83 per 1,000 participants (95% CI, 3.24, 26.45). There were 20 asthma-related deaths in the 110 studies, and 16 of those occurred among patients taking long-acting beta agonists. However, 16 of these deaths occured in SMART and while 13 deaths occured on salmeterol and 3 on the placebo; patients on ICS showed no difference in asthma related deaths (4 vs. 3).
In fact, review of much of the FDA's and the drug company's various studies seem to further add weight to the fact that 1) when used alone, LABA's can cause bad outcomes and even death and 2) when used in combination with ICS, they seem to be the most effective as well as safe option (like the NIH's 2002 recommendation).

What will happen?
This is quite hard to predict since even if the advisory committee makes a recommendation, the FDA may not necessarily follow it. The other confounding variable is that where no guideline ever recommended that LABA's be taken alone in an asthmatic, for COPD, LABA's (used BEFORE adding and ICS) remain one of the cornerstones of therapy. Thus, LABA's couldn't get removed from the market completely since their use is still deemed essential for COPD.

In my opinion, the best case scenario is that the FDA will finally but the SMART study into context: discourage the use of LABA's without an ICS by changing the boxed warning on formoterol (Foradil) and salmeterol (Serevent) to state that they should NOT be used in asthma and only used in COPD, as well as reassure patients and clinicians of the safety of LABA's plus and ICS by removing the boxed warnings from salmeterol/fluticasone (Advair), and formoterol/budesonide (Symbicort). Since there is so much political pressure on the FDA to protect the public, my guess is that the former will likely occur but the later will likely not. I do remain hopeful that the FDA will consider modified boxed warning on Advair and Symbicort to reflect the newly analized data and reassure the public, patients and physicians regarding the safety of ICS + LABA.

Bottom Line
Asthma remains a disease that causes substantial morbidity and mortality. Each day in the US there are 1300 hospitalizations, 5000 ER visits and 11 deaths due to asthma. Regardless of the outcome of the FDA advisory meeting, the FDA's recommendation or what you may hear in the media; the use of inhaled corticosteroids plus a long acting bronchodilator is one the most effective, as well as safe, options for adults and children whose asthma can not be controlled with a low dose inhaled steroid alone.


james gaulte said...

Thanks for the great review and analysis. The ghost of the incredibility poorly done SMART trial still haunts us.We can hope that the FDA actions will be as reasoned as your contribution but I am not holding my breath (pun intended).

Jordan Grumet said...

Mathew...I hope you don't mind....I reprinted part of your comments (on Rebranding) on one of my blog posts and used it for a new post.

Anonymous said...

I believe that there will be no changes to current labeling on either of the combination inhalers as the evidence suggests them to be very safe. The change may occur on the LABAs alone and state not to use in Asthma as mono-therapy but I think that is the way the labeling reads now. If in fact LABAs caused loss of life you would have seen a dramatic increase in asthma related deaths over the last 7 years and you have seen the contrary. Asthma deaths have actually decreased since the introduction of LABA containing products in the USA down from 5600 in 98 to 3780 in 04 according to the cdc..

Anonymous said...

Great review. I am a physician (psychiatrist) who has taken Advair for years. My asthma has been well controlled with the medication and I have no plans to stop taking it. The entire thing reminds me of what happened after physicians stopped prescribing antidepressants to children when the FDA put the black box warnings on SSRIs...suicide rates went up not down. I predict asthma related deaths will increase if the FDA makes a big deal out of this, as primary care docs will be less likely to prescribe the LABAs.

Mike the Geek said...

Symbicort did not do as well as Advair and had a problematic death rate. "Why, if combination products are safer, does there still seem to be a significant increase in asthma-related problems with Symbicort?" (Medscape 12-11-08)

Dr. Matthew Mintz said...

The FDA analysis compared inhaled steroids (ICS) to the two LABA products (Serevent and Foradil) and the two combo products (Advair and Symbicort). In all groups, rates of serious complications were low. Advair had a numerically lower number of serious complications then ICS, whereas Serevent, Foradil and Symbicort had a numberically higher number. However, the only comparison that was statistically different (in other words, the only comparison that was truly different) was Serevent.

Anonymous said...

Thank you for this clear and reassuring analysis. After 6 years of successful asthma maintenance with Singulair and an albuterol rescue-inhaler, I have just started Symbicort after my asthma suddenly got worse (10 attacks requiring my inhaler in 25 days!). I am feeling much, much better, breathing normally, able to sleep through the night, and generally very pleased with the results of Symbicort, but I had been worried by the warnings in the inserts about "increased risk of death". Thank you for laying out the evidence so clearly. I'll now use my Symbicort without worrying that I may be jeopardizing my health.