How the research took place
Seeking more clarity on the issue, University of Dundee School of Medicine’s Dr Ify Mordi-led team decided to approach the research from a different angle and accessed the massive local electronic database. The team explored the medical prescribing records as well as the genetic data to establish whether the use of Clarithromycin actually led to increased risk of heart problems.
The team found that as compared to the patients who had been prescribed Amoxicillin, patients taking Clarithromycin had a 31% more likelihood of being admitted to the hospital due to heart problems within a span of 14 days of starting the prescription. These patients also had a 13% more chance of being hospitalised due to a heart problem within a year after the prescription concludes.
The team also found that patients taking medicines like statins along with Clarithromycin were more likely to have a heart problem as compared to those taking statins along with Amoxicillin.
Explaining how Clarithromycin works, a statement by the University said that medications like statins and Clarithromycin use a pathway in the body which is controlled by P-glycoprotein or PGP. With the help of the genetic data, the team found that the patients having a genetic predisposition to lower PGP activity had a 40% higher risk of heart problems within up to a year after the prescription in cases of Clarithromycin as compared to Amoxicillin.
Talking about the difference between Clarithromycin and other antibiotic drugs, Dr Mordi told Financial Express Online, “Clarithromycin belongs to an antibiotic class known as “macrolides”. Others in this class include azithromycin and roxithromycin for example. These antibiotics all work in a similar way and have all had some association with increased cardiovascular risk. So our findings might be what we call a “class effect” i.e. the PGP association might apply to other macrolides also. Other antibiotics in other classes such as penicillins (e.g. amoxicillin, flucloxacillin) work in a different way to macrolides so this PGP link doesn’t apply to them.”
Overall, the study suggested that patients taking PGP inhibitors like statins or having a particular genotype should be prescribed alternative antibiotics instead of Clarithromycin.
Dr Mordi said that the team started to examine whether the association between Clarithromycin and cardiovascular events had been mediated through the PGP, which is a major pathway for the Clarithromycin metabolism.
One limitation of the study, Dr Mordi told Financial Express Online in an interview, was, “The main limitation is that this was an observational study rather than a randomised trial. Observational studies can be limited by confounding – for example, there might be something that we did not pick up that is a reason why Clarithromycin users had a higher risk. We adjusted for lots of things like previous heart attacks, age, smoking etc. but for example people that were given clarithromycin might also have had a really bad family history that we did not pick up. The key novelty in our study however was that we mitigated this by doing the genetic analysis – because your genes are given to you at random at birth, they are unaffected by things that you do, and so provide an unbiased estimate of risk. So, for example, even if there was a hidden bias where all Clarithromycin users happened to be at general practitioners (GPs) who loved prescribing PGP drugs and so had a higher risk because of this, no GP could affect their PGP genes.”
When asked about plans for the study on any other drug, the research lead said, “At present our future work may look at other macrolides to explore this further. Our study provides a framework to look at other drugs and other interactions, however our focus was driven by the clinical issue of increased cardiac risk with Clarithromycin.”
The research, funded by Chief Scientist Office, Tenovus Scotland and the Jimmie Cairncross Charitable Trust, has been published in PLOS Medicine.