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Drug Safety

, Volume 42, Issue 4, pp 529–538 | Cite as

Fluoroquinolones and Cardiovascular Risk: A Systematic Review, Meta-analysis and Network Meta-analysis

  • Einat Gorelik
  • Reem Masarwa
  • Amichai Perlman
  • Victoria Rotshild
  • Momen Abbasi
  • Mordechai Muszkat
  • Ilan MatokEmail author
Original Research Article

Abstract

Introduction

Several fluoroquinolone antibiotics have been associated with cardiac adverse effects, leading to the withdrawal of some of these agents from the market. Cardiac side effects such as QT prolongation and torsades de pointes (TdP) have also been observed with fluoroquinolones currently on the market. In order to evaluate the cardiac risk of fluoroquinolones as a class, and the comparative risk for each individual drug, we conducted a systematic review, meta-analysis, and network meta-analysis.

Methods

MEDLINE, EMBASE and the Cochrane Library were searched, up to March 2018, for randomized controlled trials, cohort studies, and case–control studies that investigated the association between fluoroquinolone treatment and the risk of cardiovascular events and cardiovascular mortality. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random effects models. Direct and indirect comparisons in network meta-analysis were performed using frequentist methods.

Results

Thirteen studies were included in our analyses. Fluoroquinolone use was associated with a statistically significant 85% increase in the risk for arrhythmia (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.22–2.81) and 71% increase in the risk for cardiovascular mortality (OR 1.71; 95% CI 1.39–2.09). Moxifloxacin ranked most likely to have the highest risk for arrhythmia (P-score 0.99) and for cardiovascular mortality (P-score 0.95) by network meta-analysis.

Conclusions

Our findings show a significant association between fluoroquinolone use and an increased risk for arrhythmia and cardiovascular mortality. Moxifloxacin ranked with the highest probability for cardiovascular adverse events. Further study is required to determine how to reduce the risk for fluoroquinolone-associated cardiac toxicity.

Notes

Compliance with Ethical Standards

Conflict of interest

Einat Gorelik, Reem Masarwa, Amichai Perlman, Victoria Rotshild, Momen Abbasi, Mordechai Muszkat, and Ilan Matok have no conflicts of interest that are directly relevant to the content of this study.

Funding

No sources of funding were used to assist in the preparation of this study.

Supplementary material

40264_2018_751_MOESM1_ESM.pdf (741 kb)
Supplementary material 1 (PDF 740 kb)

References

  1. 1.
    emc. Ofloxacin SmCP [Internet]. https://www.medicines.org.uk/emc/product/8481/smpc. Accessed 9 May 2018.
  2. 2.
    Lucena MI, Andrade JR, Rodrigo L, Salmerón J, Alvarez A, Lopez-Garrido MJ, Camargo R, Alcantára R. Trovafloxacin-induced acute hepatitis. Clin Infect Dis (Internet). 2000;30(2):400–1.CrossRefGoogle Scholar
  3. 3.
    Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. N Engl J Med (Internet). 2006;354(13):1352–61.  https://doi.org/10.1056/NEJMoa055191.CrossRefGoogle Scholar
  4. 4.
    Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother (Internet). 2002;49(4):593–6.  https://doi.org/10.1093/jac/49.4.593.CrossRefGoogle Scholar
  5. 5.
    Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG. QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine. Ann Pharmacother (Internet). 2005;39(3):543–6.  https://doi.org/10.1345/aph.1E513%0D.CrossRefGoogle Scholar
  6. 6.
    Badshah A, Janjua M, Younas F, Halabi AR, Cotant JF. Moxifloxacin-induced QT prolongation and torsades: an uncommon effect of a common drug. Am J Med Sci (Internet). 2009;338(2):164–6.CrossRefGoogle Scholar
  7. 7.
    Kannankeril P, Roden DM, Darbar D. Drug-induced long QT syndrome. Pharmacol Rev (Internet). 2010;62(4):760–81.CrossRefGoogle Scholar
  8. 8.
    Abo-Salem E, Fowler JC, Attari M, Cox CD, Perez-Verdia A, Panikkath R, et al. Antibiotic-induced cardiac arrhythmias. Cardiovasc Ther (Internet). 2014;32(1):19–25.  https://doi.org/10.1111/1755-5922.12054.CrossRefGoogle Scholar
  9. 9.
    Falagas ME, Rafailidis PI, Rosmarakis ES. Arrhythmias associated with fluoroquinolone therapy. Int J Antimicrob Agents (Internet). 2007;29(4):374–9.CrossRefGoogle Scholar
  10. 10.
    Mehrzad R, Barza M. Weighing the adverse cardiac effects of fluoroquinolones: a risk perspective. J Clin Pharmacol (Internet). 2015;55(11):1198–206.CrossRefGoogle Scholar
  11. 11.
    Bolognesi M, Bolognesi D. Ciprofloxacin-induced paroxysmal atrial fibrillation. OA Case Rep (Internet). 2014;1–3. http://www.oapublishinglondon.com/images/article/pdf/1410967708.pdf. Accessed 8 May 2018.
  12. 12.
    Lapi F, Wilchesky M, Kezouh A, Benisty JI, Ernst P, Suissa S. Fluoroquinolones and the risk of serious arrhythmia: a population-based study. Clin Infect Dis (Internet). 2012;55(11):1457–65.  https://doi.org/10.1093/cid/cis664.CrossRefGoogle Scholar
  13. 13.
    Inghammar M, Svanström H, Melbye M, Pasternak B, Hviid A. Oral fluoroquinolone use and serious arrhythmia : bi-national cohort study. BMJ. 2016;352(i843):1–8.Google Scholar
  14. 14.
    Liu X, Ma J, Huang L, Zhu W, Yuan P, Wan R, et al. Fluoroquinolones increase the risk of serious arrhythmias: a systematic review and meta-analysis. Medicine (Baltimore) (Internet). 2017;96(44):e8273.CrossRefGoogle Scholar
  15. 15.
    Moher D. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. Ann Intern Med 2009;151:264CrossRefGoogle Scholar
  16. 16.
    Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos MPT. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses (Internet). http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 2 Aug 2017.
  17. 17.
    Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ (Internet). 2011;343(7303):d5928.CrossRefGoogle Scholar
  18. 18.
    Rücker G, Schwarzer G, Krahn U, König J. Netmeta: network meta-analysis using frequentist methods. 2017. https://cran.r-project.org/web/packages/netmeta/netmeta.pdf. Accessed 9 May 2018.
  19. 19.
    Rücker G, Schwarzer G. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med Res Methodol. 2015;15(1):1–9.CrossRefGoogle Scholar
  20. 20.
    Chou HW, Wang JL, Chang CH, Lai CL, Lai MS, Chan KA. Risks of cardiac arrhythmia and mortality among patients using new-generation macrolides, fluoroquinolones, and β-lactam/β-lactamase inhibitors: a Taiwanese nationwide study. Clin Infect Dis (Internet). 2015;60(4):566–77.CrossRefGoogle Scholar
  21. 21.
    Harms H, Prass K, Meisel C, Klehmet J, Rogge W, Bereswill S, et al. Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS One (Internet). 2008;3(5):e2158.CrossRefGoogle Scholar
  22. 22.
    Rao GA, Mann JR, Shoaibi A, Bennett CL, Nahhas G, Sutton SS, et al. Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and death. Ann Fam Med (Internet). 2014;12(2):121–7.CrossRefGoogle Scholar
  23. 23.
    Zambon A, Polo Friz H, Contiero P, Corrao G. Effect of macrolide and fluoroquinolone antibacterials on the risk of ventricular arrhythmia and cardiac arrest: an observational study in Italy using case–control, case–crossover and case–time–control designs. Drug Saf (Internet). 2009;32(2):159–67.CrossRefGoogle Scholar
  24. 24.
    Ray WA, Ph D, Murray KT, Hall K, Arbogast PG, Ph D, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med (Internet). 2012;367(8):772–5.  https://doi.org/10.1056/NEJMc1207269.CrossRefGoogle Scholar
  25. 25.
    Cannon CP, Braunwald E, Mccabe CH, Grayston JT, Muhlestein B, Giugliano RP, et al. Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome. J Med (Internet). 2005;352(16):1646–54.  https://doi.org/10.1056/NEJMoa043528.Google Scholar
  26. 26.
    Bjerrum L, Andersen M, Hallas J. Antibiotics active against Chlamydia do not reduce the risk of myocardial infarction. Eur J Clin Pharmacol. 2006;62:43–9.CrossRefGoogle Scholar
  27. 27.
    Karter AJ, Thom DH, Liu J, Moffet HH, Ferrara ASJ. Use of antibiotics is not associated with decreased risk of myocardial infarction. Diabetes Care. 2003;26:2100–6.CrossRefGoogle Scholar
  28. 28.
    Luchsinger A, Pablos-me A, Knirsch C, Rabinowitz D, Shea S. Relation of antibiotic use to risk of myocardial infarction in the general population. Am J Cardiol. 2002;89(01):18–21.CrossRefGoogle Scholar
  29. 29.
    Monster TB, Johnsen SP, Olsen ML, Østergaard L, Friis S, McLaughlin JK, et al. Antibiotics and risk of first-time hospitalization for myocardial infarction: a population-based case–control study. Am J Ther (Internet). 2005;12(3):226–32.Google Scholar
  30. 30.
    Fink MP, Snydman DR, Niederman MS, Leeper KV, Johnson RH, Heard S, et al. Treatment of severe pneumonia in hospitalized patients : results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. Antimicrob Agents Chemother. 1994;38(3):547–57.CrossRefGoogle Scholar
  31. 31.
    Raschi E, Poluzzi E, Salvo F, Pariente A, De Ponti F, Marchesini GMU. Pharmacovigilance of sodium-glucose co-transporter-2 inhibitors: What a clinician should know on disproportionality analysis of spontaneous reporting systems. Nutr Metab Cardiovasc Dis (Internet). 2018;28(6):533–42.CrossRefGoogle Scholar
  32. 32.
    Inghammar M, Svanström H, Melbye M, Pasternak B, Hviid A. Oral fluoroquinolone use and serious arrhythmia : bi-national cohort study. BMJ (Internet). 2016;352(i843):1–8.Google Scholar
  33. 33.
    Zambon A, Polo Friz H, Contiero P, Corrao G. Effect of macrolide and fluoroquinolone antibacterials on the risk of ventricular arrhythmia and cardiac arrest: an observational study in Italy using case–control, case–crossover and case–time–control designs. Drug Saf. 2009;32(2):159–67.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Einat Gorelik
    • 1
    • 2
  • Reem Masarwa
    • 1
  • Amichai Perlman
    • 1
  • Victoria Rotshild
    • 1
  • Momen Abbasi
    • 3
  • Mordechai Muszkat
    • 3
  • Ilan Matok
    • 1
    Email author
  1. 1.Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
  2. 2.Department of PharmacovigilanceMinistry of HealthJerusalemIsrael
  3. 3.The Department of MedicineHadassah University HospitalJerusalemIsrael

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