Tuesday, September 23, 2008

Bad news for COPD: Why this meta-analysis should be believed (and the Avandia one should not)

OK, I may have jumped the gun a few days ago when I posted about the good news for COPD. I was reacting to the negative media reports about a study which did show that certain inhalers were bad, but seemed to forget to mention that other inhalers were life-saving! Well, this is still true; however, the bad news did just get a little worse.

The study released in today's JAMA which gave more evidence of concerns with certain COPD inhalers was picked up by a few media outlets such as USA Today and ABC News. However, it is surprising* that it hasn't created the media firestorm cause by the Avandia meta-analysis given that COPD is the 4th leading cause of death (diabetes is 6th), over 11 million US adults have COPD, and Advair (a drug used for COPD) is one of the top selling drugs in the US and world (Avandia is only #23).

What did the study show?
The study was systematic review (looked carefully to find all appropriate studies) and meta-analysis of data from 17 clinical trials studying 14,783 patients with Chronic Obstructive Pulmonary Disease (COPD, sometimes called emphysema). The study found that patients taking anticholinergic inhalers -ipratropium (Atrovent) or tiotropium (Spiriva) had a 58% increase in cardiovascular death, heart attack or stroke when compared to patients taking other meds (Advair, albuterol or placebo). Unfortunately, the data looks bad for both the older drug (ipratropium) and the newer Spiriva, when analyzed separately.

Why should I believe this study and not the Avandia one?
I have blogged multiple time about Avandia , and have criticized Dr. Nissen's meta-analysis several times. So why believe this meta-analysis and not Dr. Nissen's?

In order to determine whether a rare event is true or not, you need a study with a lot of patients. Sometimes that data is not available or doing the study is impractical. The next best thing is a meta-analysis, which combines similarly designed studies with similar patients looking at similar things, and statistically "squishes" the data together to find a true (statistically significant) finding, that could not have been found from the individual studies alone.
The authors of this study first performed a systemic review of the literature to find all published studies that were appropriate for analysis, whereas Dr. Nissen only used the GSK (makers of Avandia) studies that were published on their web site. The studies used for this meta-analysis were similarly designed, the patients were very similar (most had the same lung function) and looked at the same outcome (lung function); where some of the patients in Dr. Nissen's study didn't even have diabetes and the studies were designed to look at different things (safety, sugar control, etc.). The authors looked at the data in a variety of ways (long term vs. short term studies, taking out the one big study out of the 17, looking at different agents) and found very similar findings. Dr. Nissen, on the other hand, never explains why the rate of heart attacks in his study was LOWER in the Avandia group, but the meta-analysis showed a 43% increase in heart attack. (Another author re-analyzed Nissen's results using different methods and found no difference in heart attacks with Avandia).

Supporting Evidence
As I mentioned in my previous post, this study comes out just after another study was released that analyzed thousands of patients from the VA that showed increased deaths (11%) for patients taking ipratropium. The "good news" lost in the media was that they also found a 20% lower risk of death for patients on inhaled steroids and an 8% lower risk of death for patients on long acting β-agonists. In contrast, multiple large randomized controlled trials (as above, the most accurate way to find a true answer) show no increased rates of heart attacks with Avandia.

Biologic Plausibility
The findings have to make some sense from a biologic basis to believe them. Though the authors of this study point out that the mechanisms of how anticholinergic drugs like Atrovent and Spiriva would cause cardiovascular death, heart attacks and strokes are unknown; these medications do affect things like heart rate and rhythm. In contrast, there is really no good explanation why Avandia would cause a heart attack (though it may worsen heart failure which is not the same thing), and in fact some studies of another medication in the same class suggest that these types of diabetes medicines might actually PREVENT heart attacks.

Bottom Line: Current guidelines recommend inhaled bronchodilators as first line therapy for COPD. Given that ipratropium (Atrovent) and tiotropium (Spiriva) have been implicated in cardiac events and death, this may not be such a great idea. Interestingly, combination with an inhaled steroid is recommended only as second line. Much of the evidence from these recommendations comes from the fact that inhaled steroids (ICS) didn't improve lung function as well as the other bronchodilators. However, we have known for some time that ICS improve quality of life and reduce symptoms, and we now (very recently) know that an inhaled steroid combined with a long acting beta agonist (LABA) not only reduces COPD exacerbations, but also prevents decline in lung function and seems to prevent death. Not sure what the pulmonary experts are going to do with this new information, but it seems like ICS/LABA combination for COPD is probably the best way to go for now. If you are taking ipratoprium (Atrovent) there are likely better alternatives given it's short onset of action. If you are taking Spiriva, don't stop! Discuss this with your doctor. There is also great risk for poorly controlled COPD, and several studies that show Spiriva reduces exacerbations. The UPLIFT study is currently underway, and may have reasurring data about Spiriva. If you are diagnosed with COPD and your doctor recommends an inhaler, consider Advair or Symbicort (which is approved in the US for asthma, but like Advair, works well in COPD).

*I am not really surprised. The FDA had their own Avandia meta-analysis data and were waiting for results of the larger trials to make an overall decision. Dr. Nissen and the NEJM intentionally "scooped" the FDA and purposefully used the information to create a media frenzy which now ultimately seems not to be an issue and may have harmed some patients, since many stopped Avandia without informing their physicians.


Anonymous said...

And what about Advair's black box warning?

Dr. Matthew Mintz said...

First, there is no such thing as a "black box." This is a term created by the media. A "boxed warning" is a warning added to the label of a medication that is generally at the top and has a box around it. There is nothing "black."
The boxed warning on Advair comes from a study on salmeterol, one of the components of advair. I go into great detail on all the data regarding this on a previous post called Good News for Asthma Patients . The bottom line is that safety concerns are really only an issue with salmeterol is taken alone. When taken together with fluticasone (Advair is fluticasone +salmeterol) not only is it safe, but it is also one of the most effective medications for asthma. Since the introduction of medications like Advair the asthma death rate has declined. That, coupled with the fact that Advair in COPD patients may have actually prevented deaths suggest the medicine is safe.
The real question now is whether or not severent should be used alone in COPD. It clearly shouldn't be for asthma, but can be for COPD. Currently guidelines (which may change with this new data) recommend a bronchodilator as first line therapy. However, if you choose not to use ipra or tiotropium because if this study this leaave you with a LABA like salmeterol. On the one hand, the TORCH study did not show an increase harm rate in severent taken alone, on the other hand the data on serevent taken alone with asthmatics is worrisome. This raises the question of whether ICS/LABA (Advair, Symbicort) should be used not just in severe disease (as recommended by current guidelines), but earlier in mild to moderate disease, reserving Spiriva only when the ICS/LABA isn't working. I don't know what the guideline makers will decide, but this is where I am leaning. (Though, as above, I wouldn't recommend stopping Spiriva for now).

Anonymous said...

The Uplift data and the detailed analyses of 29 other PROSPECTIVE, placebo controlled trials with tiotropium contradict this meta-analysis. In addition, the blind faith in this meta-analysis fails to recognize its falacies. An apparent double counting of approximately 1000 patients took place, thereby rendering any statistical analysis inaccurate.

Also, the term "meta" means "many." However, the majority of the data from the analysis was pulled from a SINGLE study, the Lung Health Study. Interestingly, results were published for patients who had stopped taking medication and questions have been raised about including placebo and active comparator patients into the same grouping.

Furthermore, with funding provided by a competing drug company, we as practitioners have to question the motivation behind the publishing and also ask hard questions of our beloved JAMA publication for its lack of scrutiny.

Millions of patients worldwide have had their lives positively changed by tiotropium, dwarfing the numbers of those who may have been harmed. We all know the horrid consequence of a progressive disease such as COPD. Let's stop striking panic and fear into patients and educate them on the risk and benefits of therapies. After all, have you stopped recommending Tylenol? Think about it.....

Dr. Bruce Chester

Dr. Matthew Mintz said...

Dr. Chester,
Thanks for your comments. The meta-analysis was far from perfect. As I mentioned in this post, "If you are taking ipratoprium (Atrovent) there are likely better alternatives ... If you are taking Spiriva, don't stop! ... There is also great risk for poorly controlled COPD, and several studies that show Spiriva reduces exacerbations. The UPLIFT study is currently underway, and may have reasurring data about Spiriva."
Please also note my post following the UPLIFT study called "UPLIFTing News for COPD."
I think Spiriva is a great drug, I use it in many of my COPD patients, and will continue to do so. I think the real question is whether or not ICS/LABA should be used first followed by Spriva, or the other way around as guidelines currently suggest.

Anonymous said...

Dr. Mintz,

I regret not locating your other posts regarding this topic. Thank you for bringing it to my attention. I appreciate that you have looked at this anticholinergic issue from both sides, an activity in which we all should engage when discerning appropriate long-term maintenance therapies for our patients.

I personally have become an advocate of anticholinergic therapy prior to ICS/LABA. Cholinergic tone represents a major reversible component of COPD. In the literature, long-acting anticholinergic treatment has been shown to provide superior bronchodilation compared to LABA. In addition, patients have displayed tolerance to long-term beta agonist therapy.

Also, I like to reserve steroid therapy until I have no other options due to known long-term issues. Considering the anticholinergic first approach, I do not hesitate to give LABA/ICS if the anticholinergic does not provide adequate relief. Age of the patient also plays a role in my decision.

Thank you for the forum to express approaches to treatment and even differing viewpoints. After all, we are striving to achieve the same objective, helping patients.

Dr. Bruce Chester