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Cardiovascular outcomes associated with use of clarithromycin: population based study

BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.h6926 (Published 14 January 2016) Cite this as: BMJ 2016;352:h6926

Re: Cardiovascular outcomes associated with use of clarithromycin: population based study

As a GP registrar who regularly prescribes antibiotics I was interested to read the Wong et al. paper1 on clarithromycin and cardiovascular outcomes, and Iyer & Alexander's associated commentary2.
I disagree with the commentary in that Wong et al. contains only two, not three, separate study designs.
My main concern is that their second study simply shows, using two statistical methods, that people with cardiovascular disease who are treated for H pylori (a common cause of epigastric or oesophageal symptoms) have an elevated risk of myocardial infarction in the following 14 days. Given that epigastric symptoms are regularly associated with myocardial ischaemia3, is that surprising? The treatment they have chosen to analyse also contains a proton pump inhibitor. Given that PPIs may inhibit common antiplatelet medication4,5, and a very similar study suggests they independently increase the risk of MI by a similar magnitude6, is it fair to blame clarithromycin?
It's easy to miss these issues, since Wong et al.’s first section does compare clarithromycin prescription with amoxicillin prescription, yet it has problems of its own. The authors acknowledge that the clarithromycin cohort had greater comorbidity and polypharmacy - the fact that they went on to have higher non-cardiac mortality suggests that the authors' attempt at propensity score adjustment, although noble, may have been insufficient. Possible omitted confounders include that macrolides are often chosen for patients with penicillin allergy (who can have worse outcomes7 and higher rates of macrolide-resistant infections8), or be used second line/in addition to amoxicillin in patients who are more unwell or less likely to respond to monotherapy9. A more practical issue is Wong et al’s choice of control – would doxycycline not have been a more useful alternative?
Although I am obliged to discuss “common” and “rare but serious” medication side effects with my patients, I do not feel that the evidence presented yet justifies such a discussion about clarithromycin, as the commentary article implies.

1
Cardiovascular outcomes associated with use of clarithromycin: population based study. Wong et al.
BMJ 2016; 352
2
Cardiovascular risks associated with clarithromycin. Iyer and Alexander
BMJ 2016; 352
3
Symptom presentation of acute myocardial infarction: Influence of sex, age, and risk factors.
Culic, Viktor; Eterovic, Davor; Miric, Dinko; Silic, Nardi.
The American Heart Journal144.6 (Dec 2002): 1012-1017.
4
Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: Nationwide propensity score matched study
Charlot M.,Grove E.L.,Hansen P.R.,Olesen J.B.,Ahlehoff O.,Selmer C.,Lindhardsen J.,Madsen J.K.,Kober L.,Torp-Pedersen C.,Gislason G.H.
BMJ, May 2011, vol./is. 342/7807, 1756-1833
5
A meta-analysis of 43,432 patients: Concomitant use of proton pump inhibitor with clopidogrel is associated with increased death and myocardial infarction in patients receiving PCI
Jo S.H.,Lim H.J.,Choi Y.J.,Kim S.A.,Kim H.S.,Han S.J.,Park W.J.,Rhim C.Y.
European Heart Journal, September 2010, vol./is. 31/(495), 0195-668X (September 2010)
6
Proton pump inhibitor use represents an independent risk factor for myocardial infarction.
Shih, Chia-Jen,Chen, Yung-Tai,Ou, Shuo-Ming,Li, Szu-Yuan,Chen, Tzeng-Ji,Wang, Shuu-Jiun
International journal of cardiology, vol. 177, no. 1, p. 292-297 (November 15, 2014)
7
Adverse outcomes associated with reported penicillin allergy in patients with pneumonia and bacteremia
Reddy V.,Baman N.,Ishmael F.T.
Annals of Allergy, Asthma and Immunology, November 2012, vol./is. 109/(A127), 1081-1206
8
Factors associated with antimicrobial resistance and mortality in pneumococcal bacteremia.
Neuman, Mark I,Kelley, Meera,Harper, Marvin B,File, Thomas M,Camargo, Carlos A,EMNet Investigators
The Journal of emergency medicine, vol. 32, no. 4, p. 349-357, 0736-4679 (May 2007)
9
HPA and Association of Medical Microbiologists (2010) Management of infection guidance for primary care for consultation and local adaptation.Health Protection Agency. www.hpa.org.uk

Competing interests: No competing interests

22 January 2016
Zac BlaKe
GP Registrar
Norwich