Cardiovascular outcomes associated with use of clarithromycin

Dr Chan, Esther Wai Yin   (Principal Investigator (PI))

Professor Wong Ian Chi Kei   (Co-Investigator)

12

2015-06-01

72800

Cardiovascular outcomes associated with use of clarithromycin

antibiotics, Helicobacter Pylori eradication therapy, myocardial infarction

Cardiovascular Research

201409176255

Small Project Funding

2014

Completed

Clarithromycin is a macrolide antibiotic commonly prescribed by clinicians in the primary care setting. It is indicated for the treatment of respiratory tract infections, sexually transmitted diseases, skin and soft tissue infections, and Mycobacterium avium complex disease in patients with human immunodeficiency virus.1 It is also used to treat Helicobacter pylori infections associated with peptic ulcer disease with amoxicillin and a proton-pump inhibitor as a first-line eradication regimen.1 A recent study conducted by Schembri et al. showed that the use of clarithromycin increased the risk of cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) and community-acquired pneumonia compared to other antibiotics users after one year of exposure.2 There was also a significant association between the use of clarithromycin and cardiovascular mortality in patient with COPD versus other antibiotics users. Another recent cohort study also reported an increased risk of cardiac death (adjusted risk ratio: 1.76) associated with use of clarithromycin in Danish adults versus use of penicillin V in follow-up period of 7 days but it did not demonstrate an increased long-term cardiovascular risk.3 Cardiovascular disease is a major public health burden worldwide. According to World Health Organization, there were approximately 17.3 million people died from cardiovascular diseases in 2008. It estimated that more than 23 million people will die from cardiovascular diseases by 2030 globally.4 It was also the second leading cause of deaths in Hong Kong which accounted for 15% of all causes of mortality in 2011.5 Over the years, clarithromycin has been investigated to be the novel therapy for the secondary prevention of coronary artery disease. In order to examine the effects of clarithromycin on cardiovascular diseases, randomized controlled trials (RCTs) were conducted.6-8 Among these, the first RCT showed that clarithromycin treatment duration of three months appeared to reduce the risk of cardiovascular outcomes in 1.5 years.6 However, another RCT showed short-term treatment did not significantly reduce the rate of cardiovascular events compared with placebo among patients undertaking coronary artery bypass graft with follow-up of 2 years.8 On the contrary, a significantly higher risk of cardiovascular mortality was reported over 3 years and also higher all-cause mortality among patients with coronary heart diseases receiving a two week course of clarithromycin once daily versus placebo in 6 years.7 9 A meta-analysis concluded that clarithromycin led to a significantly higher all-cause mortality (hazard ratio: 1.21) in the clarithromycin treated group of patients versus placebo in six-year follow-up.9 A study with cohort and nested case-control design conducted in Italy also reported significantly higher risk of receiving new antiarrhythmic prescriptions (proxy for arrhythmia) among new clarithromycin users when compared with the subjects who did not receive clarithromycin.10 Some case studies also reported the association between clarithromycin and cardiovascular events such as the prolongation of QT interval, torsades de pointes, and arrhythmia.11-15 In summary, recent studies report an increased risk of cardiovascular events among patients taking clarithromycin. However, most of the studies recruited subjects who were at high cardiovascular risk. Given the uncertain nature of any increased cardiovascular risk with clarithromycin, and the surprising finding of a persistent effect well beyond the period of exposure, this proposed study aims to: - Examine the utilisation pattern of clarithromycin in the United Kingdom, following a study conducted in the Hong Kong setting. - Investigate the association between myocardial infarction and the current, recent and past use of the clarithromycin compared with amoxicillin using cohort study design - Investigate the association between all-cause, cardiovascular mortality and non-cardiovascular mortality and the current, recent and past use of the clarithromycin compared with amoxicillin using cohort study design - Investigate the association between incident myocardial infarction and the current, recent and past use of the clarithromycin-containing Helicobacter Pylori eradication regimen using self-controlled case series design References 1. Zuckerman JM. Macrolides and ketolides: azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am 2004;18(3):621-49. 2. Schembri S, Williamson PA, Short PM, et al. Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies. BMJ 2013;346:f1235. 3. Svanstrom H, Pasternak B, Hviid A. Use of clarithromycin and roxithromycin and risk of cardiac death: cohort study. BMJ 2014;349:g4930. 4. World Health Organization. Cardiovascular disease. 2014 [Last accessed on: 14 November 2014]; Available from: http://www.who.int/cardiovascular_diseases/en/. 5. Centre for Health Protection. Heart diseases. 2012 [Last accessed on: 14 November 2014]; Available from: http://www.chp.gov.hk/en/content/9/25/57.html 6. Sinisalo J, Mattila K, Valtonen V, et al. Effect of 3 months of antimicrobial treatment with clarithromycin in acute non-q-wave coronary syndrome. Circulation 2002;105(13):1555-60. 7. Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ 2006;332(7532):22-7. 8. Berg HF, Maraha B, Scheffer GJ, et al. Treatment with clarithromycin prior to coronary artery bypass graft surgery does not prevent subsequent cardiac events. Clin Infect Dis 2005;40(3):358-65. 9. Gluud C, Als-Nielsen B, Damgaard M, et al. Clarithromycin for 2 weeks for stable coronary heart disease: 6-year follow-up of the CLARICOR randomized trial and updated meta-analysis of antibiotics for coronary heart disease. Cardiology 2008;111(4):280-7. 10. Corrao G, Botteri E, Bagnardi V, et al. Generating signals of drug-adverse effects from prescription databases and application to the risk of arrhythmia associated with antibacterials. Pharmacoepidemiol Drug Saf 2005;14(1):31-40. 11. Kundu S, Williams SR, Nordt SP, et al. Clarithromycin-induced ventricular tachycardia. Ann Emerg Med 1997;30(4):542-4. 12. Lee KL, Jim MH, Tang SC, et al. QT prolongation and Torsades de Pointes associated with clarithromycin. Am J Med 1998;104(4):395-6. 13. Hensey C, Keane D. Clarithromycin induced torsade de pointes. Ir J Med Sci 2008;177(1):67-8. 14. Curtis LH, Ostbye T, Sendersky V, et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. Am J Med 2003;114(2):135-41. 15. Kamochi H, Nii T, Eguchi K, et al. Clarithromycin associated with torsades de pointes. Jpn Circ J 1999;63(5):421-2.