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

Posted Sep 24 2008 11:38am
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?

Methodology
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.
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