Common antibiotic linked to 'tiny' rise in heart dea...

An antibiotic given to millions of people in the UK to treat chest infections has been linked to an increased risk of heart death, report The Daily Telegraph and The Independent.

A Danish study of three antibiotics found the risk of death from any heart condition while taking the antibiotic clarithromycin is slightly higher than with penicillin V.

Clarithromycin is used for respiratory infections, and 2.2 million doses were prescribed in England in 2013. However, it is not recommended for people with abnormal heart rhythms.

Researchers compared the number of people who had a heart-related death after being put on a course of either clarithromycin, roxithromycin (not used in the UK) or penicillin.

The study, published online in the British Medical Journal, found there were an extra 37 cardiac deaths per 1 million courses of clarithromycin compared with penicillin.

But the risk was still very low. As this was a cohort study, it cannot prove that any of these deaths were as a result of taking clarithromycin, as it did not account for all of the other factors that could have influenced the results.

In particular, major risk factors for heart conditions such as smoking and obesity were not included in the analyses. When all factors the researchers did record were accounted for, there was no longer any statistically significant difference between clarithromycin and penicillin.

This study should not cause unnecessary concern – although there appears to be an increase in risk, this is tiny, at 0.01%.

Where did the story come from?

The study was carried out by researchers from the Statens Serum Institut in Copenhagen. They report there was no funding.

It was published in the peer-reviewed British Medical Journal (BMJ). It is available to read on the BMJ website.

The media reported the story reasonably accurately, but on the whole failed to point out quite how low the risk of cardiac death is on these antibiotics.

There were good quotes from UK experts about the fact that all drugs have some side effects and should therefore only be taken if they are really needed – this is particularly important for antibiotics given the increase in antibiotic resistance.

What kind of research was this?

This was a cohort study. It aimed to see if there was an increased risk of cardiac death while taking clarithromycin or roxithromycin compared with penicillin V.

Penicillin V is an antibiotic used for treating bacterial infections of the ear, throat, chest, skin and soft tissues.

Clarithromycin is an antibiotic used to treat bacterial chest infections, throat or sinus infections, skin and soft tissue infections, and Helicobacter pylori associated with peptic ulcers. It is not recommended for people with abnormal heart rhythms.

Roxithromycin is a similar type of antibiotic, but it is not used in the UK. All three are also used as prophylactic medication to prevent infections for people who are immunocompromised.

As this was a cohort study, it cannot prove that clarithromycin caused any cardiac deaths. This is because it does not take into account confounding factors that may have influenced the results. A randomised controlled trial would be required to prove causation.

What did the research involve?

The researchers compared the number of people who had a cardiac death during or in the 30 days after an outpatient course of either clarithromycin or roxithromycin, compared with penicillin V.

The nationwide Danish National Prescription Registry was used to identify all adults aged 40 to 74 who collected prescriptions for each antibiotic between 1997 and 2011.

Each time a person had a prescription of one of the drugs this was included in the analysis as long as they were not in hospital or had been prescribed an antibiotic in the previous 30 days. This means some people would have been included who had more than one antibiotic prescription.

The researchers collected data on cardiac deaths from the Danish Register of Causes of Death and looked at whether there was an association between taking either clarithromycin or roxithromycin compared with penicillin V, and having a cardiac death.

They looked at whether people had a cardiac death during the following two periods:

the seven days of likely antibiotic use from the start date of the prescription
eight to 37 days after the start date of the prescription

The researchers excluded people with serious disease (including cancer, neurological diseases or liver disease) and those deemed to be at high risk of death from non-cardiac causes.

They adjusted their analyses for a number of confounders, including sex, age, place of birth, time period, season, medical history, prescription drug use in the previous year, and use of healthcare in the previous six months.

What were the basic results?

There were 285 cardiac deaths during the first seven days after antibiotic prescription from a total of more than 5 million antibiotic prescriptions that met the study inclusion criteria. Of these, there were:

18 deaths during 160,297 courses of clarithromycin (0.01%), incidence rate of cardiac death 5.3 per 1,000 person years
235 deaths during 4,355,309 courses of penicillin V (0.005%), incidence rate of cardiac death 2.5 per 1,000 person years
32 deaths during 588,988 courses of roxithromycin (0.005%), incidence rate of cardiac death 2.5 per 1,000 person years

After taking into account sex, age, cardiac risk score and the use of other drugs that are metabolised in a similar way, clarithromycin was associated with a 76% higher risk of cardiac death than penicillin V (adjusted rate ratio 1.76, 95% confidence interval [CI] 1.08 to 2.85).

The researchers say this would be equivalent to 37 extra cardiac deaths per 1 million treatment courses associated with clarithromycin compared with penicillin V (95% CI, 4 to 90). Roxithromycin was not associated with an increased risk.

The risk was higher in women on clarithromycin, (adjusted rate ratio 2.83 [95% CI 1.50 to 5.36]) compared with men (adjusted rate ratio 1.09 [95% CI 0.51 to 2.35]), although the difference was not statistically significant.

When the researchers performed additional analysis, where they matched people who had taken clarithromycin with people who had taken penicillin, according to sex, age, place of birth, time period, season, medical history, prescription drug use in the previous year and use of healthcare in the previous six months, they found the increase in risk of cardiac death with clarithromycin compared with penicillin was no longer statistically significant (rate ratio 1.63, 95% CI 0.87 to 3.03).

Between 8 and 37 days after antibiotic prescription, when it was assumed that people had finished taking antibiotics, there were 364 cardiac deaths. Of these, there were:

14 deaths after clarithromycin, incidence rate 1.3 per 1,000 patient years
308 deaths after penicillin V, incidence rate 1.0 per 1,000 patient years
42 deaths after roxithromycin, incidence rate 1.0 per 1,000 patient years

Neither clarithromycin nor roxithromycin had an increased risk of cardiac death compared with penicillin after the presumed seven-day course.

How did the researchers interpret the results?

The researchers concluded this study "found a significantly increased risk of cardiac death associated with current use of clarithromycin, but not roxithromycin".

However, they also acknowledged that, "Before these results are used to guide clinical decision making, confirmation in independent populations is an urgent priority given the widespread use of macrolide antibiotics".

Clarithromycin and roxithromycin both belong to the macrolide class of antibiotics.

Conclusion

The conclusion that the risk of cardiac death during the use of clarithromycin is 76% higher than that for penicillin V was based on a small number of cardiac deaths. In fact, it occurred during 0.01% of prescriptions of clarithromycin, compared with 0.005% during prescriptions for penicillin V.

A death rate just a bit higher than a very small death rate is still very small. This means that from an individual point of view, the risk of cardiac death from taking either antibiotic is minimal.

This study does not prove clarithromycin caused any cardiac deaths. It only showed a very small increased risk of cardiac death in the seven days after the prescription was collected in a select group of people. This did not include:

antibiotic use in hospitals
people with serious illnesses
long-term prophylactic use (to prevent infections), such as for those who are immunocompromised
people who did not improve and required an alternative antibiotic

The study also has several other limitations, including:

major risk factors for cardiac death, such as smoking and obesity, were not taken into account
the reason for taking each antibiotic was not known – clarithromycin is used for more types of infections than penicillin V, which may have influenced the results
clarithromycin is commonly used for people who are allergic to penicillin, but this factor was not assessed in the study
it was assumed that people who collected their prescriptions took the medication as prescribed for seven days

Also, when the researchers performed additional analysis, where they matched people who had taken clarithromycin with people who had taken penicillin according to sex, age, place of birth, time period, season, medical history, prescription drug use in the previous year and use of healthcare in the previous six months, they found the increase in risk of cardiac death with clarithromycin was no longer statistically significant.

Although it is already known clarithromycin can have an effect on the rhythm of the heart and is not recommended for people who have irregular heart rhythms, the study did not specifically look at cardiac death caused by an abnormal rhythm, but instead grouped all causes of death related to heart problems. This further limits the ability to establish a link between how clarithromycin might be increasing the very small risk.