Tuesday, August 13, 2013

Azithromycin's Black Box Warning - Shouldn't be Yellow?

In May of 2012 the NEMJ published an article about the cardiac risks of Azithromycin. This fake science was the base for recent decision of the FDA to issue a black box warning, which in my opinion was an overboard and wrong move. Last year I replied with this editorial, which I admit, it was a little harsh with a touch of my usual sarcasm, that's probably why it didn't get published. Nevertheless, I just want to add it to my blog for those who want read and think outside this black box (warning).

First, read it from the NEJM site:

http://www.nejm.org/doi/full/10.1056/NEJMoa1003833?query=emergency-medicine

According to the authors, it seems like you are almost 2.5 times more likely to die a cardiovascular death after a course of "Azithro" than you are after taking 7 days of Amoxil, and almost 3 times compared to no antibiotics at all. Which means that even amoxicillin has a hazard ratio of 0.5 compared to not taking any antibiotics. However... Let's put this in perspective, shall we?  Using the numbers provided in the result section, you need to prescribe 1,000,000 Z-packs to kill 47 patients with low cardiovascular risk and 245 with high cardiovascular risk. That means that even in the worse case scenario, the number needed to kill by one course of azithromycin is 1 per 4081 compared with 1 in 10,202 of amoxicillin. Hmmm... Do you want a more ridiculous number? - OK. Assuming that you prescribe Azithromycin once a day every day of the year; you need to practice for 11 years, non-stop and with no days off to kill one patient with high cardiovascular risk and 58 years for the low cardiovascular risk patients. Amazing, isn't? - To me this doesn't sound too bad when compared with the 27% mortality rate of sepsis with severe pneumonia or with other therapies we use, like warfarin that clearly has a higher risk of harm associated with it. What I would like to see is more details about the high risk patients. As statisticians say "The devil is in the details". In the first place, we don't give antibiotics to healthy people (so I hope), and using healthy patients as denominator just doesn't seem right. Then, there is the fact that Azithro is considered a "stronger" antibiotic compared to amoxi being a better choice for sicker patients. And why is it that Azithromycin is in the guidelines for the treatment of pneumonia and not amoxicillin? Was the choice of Azithromycin a marker or more severe disease and therefore prescribed to sicker patients who had more risk of death regardless of the antibiotic choice? - I don't know. This article doesn't answer that.

There is no question that antibiotics (and for that matter, any medication) will hurt some patients, that is just reality. Some will have minor problems and some others will even die as direct consequence of the drug. About 10 years ago my cardiology professor and I wrote an editorial about several types of medications and the risk of CV death by long QT syndrome (Headache. 2003 Jul-Aug;43(7):809-10.), and even then, we found that commonly prescribe drugs will have that effect in genetically susceptible patients. It has to do with some weird channelopathy of the slow potassium channels in the myocardium and these folks will just drop death from a malignant dysrrhythmia. This effect is significantly increased with certain types of medications and macrolides are one of them. Thankfully, the susceptibility due to genetic predisposition is very rare, so rare, that we don't routinely screen patients for channelopathies, do we? However, a sick heart is a sick heart regardless of the cause and these patients will have higher mortality even if you give them gummy bears for their presbyopia and then an article will be published urging a black box warning for gummy bears. The bottom line is that the possible harm (extremely unlikely) most be weigh with benefits (more likely) and to ask the questions: Is the patient at risk? Taking other QT prolonging meds? Is there history of sudden cardiac death in the family? - In the very few cases with a positive answer, a screening EKG should suffice to make your antibiotic choice.

Finally, this black box warning forces the question... Is the FDA black boxing azithromycin b/c a new "safer" macrolide will be soon introduced to the market in-sync with the Azithromycin patent expiration? Hmmmm. I know I am being cynical... :p

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