Journal Club Presentation

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JournalClub
Preparedby:
Dr. Bhargav Darji
2nd Year Resident
Pharmacology Dept.
GMC, Surat.
“Fluoroquinolones and Cardiovascular Risk: A
Systematic Review, Meta-analysis and Network
Meta-analysis”
Author: Einat Gorelik, Reem Masarwa, Ilan Matok et al.
Journal: Drug Safety
April 2019, Volume 42, Issue 4, pg. 529–538
TheOfficialJournalofInternationalSocietyof Pharmacovigilance

2. 1. INTRODUCTION
 Fluoroquinolone antibiotics have a widespread use and are commonly used for a variety of
infections, including
o respiratory tract infections,
o urinary tract infections,
o skin and soft tissue infections
 Several fluoroquinolones have been removed from the market due to safety issues such as
o Hepatoxicity (e.g., trovafloxacin),
o Hypoglycemia (e.g., gatifloxacin),
o Cardiotoxicity (e.g., grepafloxacin).
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3.  Cardiac side effects such as QT prolongation and TdP have also been observed.
o Proposed mechanism: blockade of the rapid delayed rectifier potassium current (IKr).
 The available data suggests that
o Moxifloxacin carries the greatest risk of QT prolongation and TdP.
o Ciprofloxacin appears to have lowest risk for QT prolongation and TdP.
o Yet, several reports of ciprofloxacin cardiotoxicity have been published.
 A single Meta-Analysis (Liu et al.) has reported that, as a class, fluoroquinolones are associated
with an increased risk of serious arrhythmia.
 Nevertheless, the relative risk for cardiac toxicity with the use of individual fluoroquinolone
agents has not been evaluated by any of the published studies.
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4.  Hence, conducted a systematic review, a
meta-analysis, and a network meta-analysis to
estimate the cardiac risk of
o Fluoroquinolones as a class, and
o comparative risk for 3 commonly used
individual fluoroquinolones
• Moxifloxacin
• Levofloxacin
• Ciprofloxacin
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5. 2. METHODS
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2.1 Data Source & Searches
 Systematic review was performed (as per PRISMA
2009 Guidelines) by searching all publications
indexed in
o MEDLINE (from 1966)
o EMBASE (from 1974)
o Cochrane Library (from 1993)
 Search performed on March 14, 2018, with no
date restriction.
 Search included RCT, Cohort & Case Control
studies.
 Searches were performed using
o MeSH terms
o Free keywords
 A manual search of reference lists of review
articles and original studies was performed to
identify additional reports.

6. 2.2 Selection Criteria
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Inclusion Criteria Exclusion Criteria
 Included if published studies reported on the
risk of arrhythmia, cardiovascular mortality
or MI in fluoroquinolone users with no time
limitation.
 Included observational studies and RCTs.
 Included most informative and recent
publication in the analysis when results of a
study were reported in more than one
publication.
 Excluded case reports, case series, reviews,
expert opinion, editorials.
 Excluded if articles had insufficient published
data for determining an estimate of RR or OR
and CI.
 Excluded articles involving populations with
HIV, TB, sepsis and ICU patients.
 Excluded studies in which the only
comparison group was macrolide users.

7. 2.3 Data Extraction & Quality Assessment
 The data were extracted & evaluated by two independent reviewers (EG and RM).
 Disagreements were resolved through consensus or referral to a third reviewer (IM) when
needed.
 The quality of the observational studies was assessed using the Newcastle–Ottawa Quality
Assessment Scale (NOS) scoring.
 The risk of bias for RCTs was assessed using the Cochrane tool.
2.4 Outcomes
 Odds ratios were determined for arrhythmia, cardiovascular mortality and MI.
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8. 2.5 Statistical Analysis
 Pooled ORs and corresponding 95% CIs were calculated for each primary outcome.
 Heterogeneity of the data was quantified using the Q statistic and the I2 statistic.
 Effect sizes of fluoroquinolones as a class were pooled using random-effects models.
 Network meta-analysis was conducted according to PRISMA-NMA 2015.
 Arrhythmia and cardiovascular mortality risks of fluoroquinolones were ranked using P-scores
derived from network point estimates and standard errors.
 Inconsistency was assessed by using the Q statistic and comparing the results from direct and
indirect estimates.
 Subgroup analysis was performed according to study design: observational and interventional.
 Finally, sensitivity analysis and sub-analysis of studies were also performed.
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9. 3. RESULTS
3.1 (a) Selection Process
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10. 3.1 (b) Study Characteristics
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11. 3.2 Meta-Analysis
 Arrhythmia
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 6 studies with 4,507,132 participants (three cohort studies, two case–control studies, and one
RCT) reported arrhythmia among fluoroquinolone users.
 The pooled analysis showed a significant association between fluoroquinolone use and an
increased risk for arrhythmia (OR 1.85 [95% CI 1.22–2.81]) I2 = 87%.

12.  Cardiovascular Mortality
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 Myocardial Infarction

13. 3.3 Network Meta-analysis
 Arrhythmia
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14.  Cardiovascular Mortality
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15. 4. DISCUSSION
 Results of Meta-Analysis indicate
o An association between the use of fluoroquinolones and the risk for arrhythmia and
cardiovascular mortality.
 Results of Network Meta-Analysis indicate
o Moxifloxacin treatment was associated with the highest probability to be associated
with risk for both arrhythmia and cardiovascular mortality
o Ciprofloxacin was associated with the lowest probability to be associated with the risk
for both outcomes.
 These results are consistent with Liu et al.’s results
o But Liu et al. included in their analysis a study based on the US FDA adverse event
reporting system (FAERS).
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16.  In Network Meta-Analysis,
o Higher risk observed with moxifloxacin use is consistent with in-vitro findings.
o Higher risk was observed for levofloxacin compared with ciprofloxacin in analysis
of both the outcomes.
o Findings are consistent with the fact that ciprofloxacin is often considered as
having the lowest potential to cause CVS side effect.
o Results of this analysis suggest a very weak association between the use of
fluoroquinolone antibiotics and MI.
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17.  Strengths:
o The results are generalizable.
o The subgroup analyses performed support these findings.
o First to conduct indirect comparisons using a network meta-analysis.
 Limitations:
o Study was not designed to explore the interaction between co-morbidity and
fluoroquinolones’ cardiovascular adverse effects.
o Confounding is a possible limitation of observational studies.
o No information regarding important lifestyle factors in many studies.
o Evidence of high heterogeneity among trials for some of the outcomes.
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18. 5. CONCLUSION
 Findings show a significant association between fluoroquinolone use and increased risk for
arrhythmia and cardiovascular mortality.
 Risk is especially pronounced with moxifloxacin, which was associated with a 2- to 3-fold higher
risk for these outcomes.
 Due to widespread use of FQs, findings are relevant to healthcare professionals as they provide
the best available evidence on the cardiac risk profile.
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Thank you