Clarithromycin alert: increased heart disease mortality

​​​​​The FDA just released a drug safety communication on clarithromycin: "Potential increased risk of heart problems or death in patients with heart disease". see https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm597862.htm​ ​

Details:

--this safety alert is based on the results of a 10-year followup study (the CLARICON study) finding that clarithromycin was associated with increased risk of heart problems or death in those with underlying coronary heart disease

Background:

--the initial study was the CLARICON study, published in BMJ in 2005 (see doi:10.1136/bmj.38666.653600.55), which was testing the hypothesis that a 2-week course of clarithromycin would decrease cardiac events. 4373 patients aged 18-85 who had a diagnosis of MI or angina and stable CAD were randomized to clarithro 500 mg/d vs placebo.  the impetus for this study was the well-documented association between Chlamydia pneumoniae and CAD, even with findings of this bug inside the atherosclerotic plaque. and the idea was that treating a potential infection with clarithro would then decrease CAD clinical events. But, alas, though there was no significant change in the primary outcome (composite of all-cause mortality, MI, or unstable angina) during 3 years of followup, there was a significant 27% increase in mortality and a 45% increase in cardiovascular mortality. the 6-year data still confirmed a 21% increase in mortality. A 10-year followup study (Winkel P. Int J Cardiol. 2015 Mar 1; 182: 459) noted a statistically significant 10% increase in all-cause mortality and a 19% increase in cerebrovascular disease. These increases in cardiovascular mortality in the 1st 3 years were restricted to patients not on a statin (and only 41% of these patients with CAD were on a statin!!!, but this was an old study); though, interestingly, in the last 4 years of this extended 10-yr study, cardiovascular death rates were 36% lower in the clarithromycin group. this last finding may be because those who were at particularly high cardiac risk died earlier, leaving a healthier cohort for the later years. [though typically it is still better to live longer.....]. By the way, this study does not definitively rule-out C pneumoniae as a reversible cardiac risk factor: many of these patients in the study may not have had active C pneumoniae infections, since only 64% of the patients had antibodies to C pneumoniae and these antibodies do not confirm active infection, so even some benefit from elimination of C pneumoniae may have been dwarfed by the negative effects of the clarithromycin]

--of the 6 observational studies, 2 found evidence of long-term risks from clarithromycin, 4 did not

--a meta-analsyis of 17 RCTs of antibiotics for patients with CAD did find that clarithro was associated with increased risk of cerebrovascular disease [this was mentioned in the paper, though i could not find the meta-analysis itself to confirm]

--but, for those of us who aggressively test and treat H Pylori infections with clarithro, there was a study of 5265 patients with pre-existing CAD that found no increase in all-cause mortality (Anderson SS. Cardiol. 2010; 116: 89). not sure how to interpret this in light of the above, but perhaps some solace.  see http://gmodestmedblogs.blogspot.com/2018/01/h-pylori-ppi-use-and-gastric-cancer.html for the array of blogs arguing for aggressive treatment of H Pylori to prevent gastric cancer

--no clear mechanistic reason that the risk of death was higher with clarithro​. though clarithro is concentrated in macrophages and macrolide antibiotics stimulate macrophage growth, perhaps leading to unstable plaques susceptible to rupture. ?arrhythmias from QTcprolongation

--though overall mortality is not increased in some studies with azithromycin (which is heralded as being safer than clarithro), an older blog commented on the higher incidence of MI in some studies (see http://gmodestmedblogs.blogspot.com/2014/06/azithromycin-for-pneumonia-and.html ). And the FDA did release warnings about prolonged QTc (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404501/ for a review of several studies)

so, the FDA is now highlighting the potential cardiac risk of clarithro (seems like that might have been done in 2005.....).  though it seems that patients with CAD are quite likely to be on a statin now, which seems to negate the potential adverse cardiovascular effects of clarithromycin. But, as with all antibiotics, they should be used minimally and with ones which have the least broad antibiotic effect that is appropriate for the infection. or risk adverse effects on the poor microbiome being unnecessarily altered, bugs becoming resistant etc. 

see:

http://gmodestmedblogs.blogspot.com/search/label/microbiome for several articles on microbiome changes with antibiotics

http://gmodestmedblogs.blogspot.com/2018/01/antibiotic-use-in-kids-narrow-spectrum.html for a retrospective study of kids, finding that broad spectrum antibiotics do not work better than narrow spectrum ones

http://gmodestmedblogs.blogspot.com/2017/07/take-full-course-of-antibiotics.html for an argument that at this time, given shifts in antimicrobial colonization, it may be better to have patients NOT take a full course of antibiotics

http://gmodestmedblogs.blogspot.com/search/label/antibiotic%20resistance for articles on increasing antimicrobial resistance

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