Article Text
Abstract
Aim Conflicting results have been reported regarding the association between fluoroquinolones (FQs) and the risk of out-of-hospital cardiac arrest (OHCA). In particular, it has not become clear whether OHCA in FQ users is related to the inherent comorbidities or whether there is a direct pro-arrhythmic effect of FQs. Therefore, we studied the relation between FQs and OHCA in the general population.
Methods Through Danish nationwide registries, we conducted a nested case–control study with OHCA cases of presumed cardiac causes and age/sex/OHCA date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the OR with 95% CI of OHCA comparing FQs with amoxicillin.
Results The study population consisted of 46 578 OHCA cases (mean: 71 years (SD: 14.40), 68.8% men) and 232 890 matched controls. FQ was used by 276 cases and 328 controls and conferred no increase in the odds of OHCA compared with amoxicillin use after controlling for the relevant confounders (OR: 0.91 (95% CI: 0.71 to 1.16)). The OR of OHCA associated with FQ use did not vary significantly by age (OR≤65: 0.96 (95% CI: 0.53 to 1.74), OR>65: 0.88 (95% CI: 0.67 to 1.16), p value interaction=0.7818), sex (ORmen: 0.96 (95% CI: 0.70 to 1.31), ORwomen: 0.80 (95% CI: 0.53 to 1.20), p value interaction=0.9698) and pre-existing cardiovascular disease (ORabsent: 1.02 (95% CI: 0.57 to 1.82), ORpresent: 0.98 (95% CI: 0.75 to 1.28), p value interaction=0.3884), including heart failure (ORabsent: 0.93 (95% CI: 0.72 to 1.22), ORpresent: 1.11 (95% CI: 0.61 to 2.02), p value interaction=0.7083) and ischaemic heart disease (ORabsent: 0.85 (95% CI: 0.64 to 1.12), ORpresent: 1.38 (95% CI: 0.86 to 2.21), p value interaction=0.6230).
Conclusion Our findings do not support an association between FQ exposure and OHCA in the general population. This lack of association was consistent in men and women, in all age categories, and in the presence or absence of cardiovascular disease.
- Death, Sudden, Cardiac
- Epidemiology
- Pharmacology
Data availability statement
No data are available. The data underlying this article cannot be shared publicly due to ethical/privacy reasons.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Out-of-hospital cardiac arrest (OHCA) remains an elusive public health burden that accounts for 50% of all deaths from cardiovascular causes in the affluent world.
A few observational studies suggested that fluoroquinolones (FQs) may increase the risk of cardiac arrhythmia, but the evidence from these studies is inconclusive because data underlying these findings have important limitations (eg, confounding by indication, small sample size and misclassification of the outcome) and have yet to be reproduced.
WHAT THIS STUDY ADDS
The relation between FQs and OHCA risk is studied in a large nationwide nested case–control study by including data from more than 45 000 OHCAs of presumed cardiac cause in Denmark.
FQs are not significantly associated with increased risk of OHCA compared with amoxicillin, despite users of FQs being older and having a higher comorbidity burden than users of amoxicillin.
This lack of association was consistent in men and women, in all age categories, and in the presence or absence of cardiovascular disease.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Our findings do not support an increased risk of OHCA in users of FQs. Our data are noteworthy, given that FQs are relatively commonly prescribed antibiotics in the clinical practice.
Introduction
Out-of-hospital cardiac arrest (OHCA) remains an elusive public health burden that accounts for 50% of all deaths from cardiovascular causes in the affluent world.1 OHCA is predominantly caused by cardiac arrhythmias that occur most frequently in the setting of structural heart disease.2 Many widely used drugs that impair cardiac repolarisation by blocking cardiac potassium channels and prolong the QT interval on the ECG may increase the risk of OHCA based on torsade de pointes arrhythmia.3 This applies not only to drugs used for cardiac disease, but also to drugs prescribed to treat non-cardiac disease.4–8 The latter is important considering that non-cardiac drugs consist of many widely used drugs in the clinical setting (eg, antipsychotics, antibiotics4–8) which are likely to be prescribed by non-cardiologists who may not be aware of the possible OHCA risk and/or have less means to monitor this risk.5
Fluoroquinolones (FQs) are a class of widely used antibiotics with broad-spectrum activity against both gram-positive and gram-negative bacteria.9 10 While being generally well tolerated, the use of FQs is associated with prolongation of the QT interval11 12 and several studies suggested an increased risk of cardiac arrhythmias in patients treated with FQs.13 14 However, confounding by indication may play an important role in the referenced studies reporting increased risk of cardiac arrhythmia in patients using FQs since exposure to FQs was compared with no use of antibiotics. Consequently, it remains questionable whether the increased risk of cardiac arrhythmia in patients using FQs is caused by FQ alone or by the underlying inflammatory diseases. If increased risk of cardiac arrhythmia in patients using FQs is the result of the underlying inflammatory diseases, we expect that the risk on cardiac arrhythmias and OHCA with FQ exposure not to be different from patients using other antibiotics. Establishing whether FQs are or are not associated with increased OHCA risk is of significant public health importance as FQs are among the most commonly prescribed antibiotics worldwide.15 Accordingly, using nationwide Danish registries, we aimed to study whether use of FQs was associated with increased odds of OHCA when compared with amoxicillin. The reference category consisted of users of amoxicillin as amoxicillin has not been shown to have adverse cardiac effects including QT prolongation.16 17 Further, we evaluated the role of important risk factors that may enhance the QT interval-prolonging effects of FQs by performing stratified analyses according to sex, age and cardiovascular disease, including ischaemic heart disease and heart failure.
Methods
Data sources and definitions
Each Danish citizen is registered with a unique personal identification number upon birth or immigration that enables linkage of individual-level data between nationwide registries. This allows to follow each citizen longitudinally and to conduct large-scale epidemiological research with nationwide coverage.18 For this study, data from the following registries were used: (1) the Danish Civil Registry providing data on sex, age and vital status18; (2) the Danish National Patient Registry holding data on all hospital admissions with diagnoses and procedures coded according to the International Classification of Diseases 10th revision (ICD-10)19; (3) the National Prescription Register providing data on complete drug dispensing records that are classified according to the Anatomical Therapeutic Chemical classification code (ATC code)20; (4) the Danish Registry of Causes of Death containing data with respect to the primary and contributing causes of death21; and (5) the Danish Cardiac Arrest Registry, which is an ongoing nationwide registry containing data on all patients who suffered an OHCA in Denmark since June 2001.22 OHCA is defined as a condition of cardiac arrest where an ambulance has been mobilised, and where cardiopulmonary resuscitation has been attempted, either by a bystander or emergency medical service (EMS) personnel. The capture of cardiac arrest cases is complete as EMS is activated for all clinical emergencies in Denmark and EMS personnel must complete a case report for every attended OHCA, thereby providing information about important factors related to the OHCA. OHCAs in the registry are categorised as being of presumed cardiac or non-cardiac cause. This categorisation was conducted using diagnosis codes from death certificates and discharge diagnoses from index hospitalisation. OHCAs with diagnosis codes for cardiac disease, unknown disease or unexpected collapse were defined as being of presumed cardiac cause. These registries have been previously used and described by this research group.22–26
Study design
We performed a nested case–control study using a nationwide cohort of individuals in the period between 1 June 2001 and 31 December 2019. Cases were individuals who suffered OHCA of presumed cardiac cause within the study period and were matched in 1:5 ratio to control subjects without OHCA from the general population based on sex, age and index date (date of OHCA for cases or corresponding date from controls). The matching was performed under the condition that controls were alive on the index date. This study design has been previously used by this research group.22 23
Exposure of interest and covariates
The exposure of interest was the use of FQs defined as any dispensed prescription within 14 days prior to the index date (see online supplemental table 1 for ATC codes). Because FQs are generally recommended to be prescribed for 7–14 days, we used an exposure window of 14 days. To minimise the risk of bias, we used an active comparator design in which the non-exposed category included the use of amoxicillin which was defined similarly to FQs. Subjects were classified into one of the following hierarchical categories based on the current 14-day history: (1) FQ users (alone or in combination with other antibiotic drugs), (2) amoxicillin users and (3) non-users of FQs or amoxicillin. Next, the following comorbidities were identified in a 10-year lookback period from index date using the primary or secondary diagnosis registered during hospital contact: ischaemic heart disease, heart failure, atrial fibrillation, cerebrovascular disease, peripheral artery disease, diabetes mellitus, chronic obstructive pulmonary disease and chronic kidney disease. Since the diagnosis code of diabetes mellitus has a low sensitivity in the Danish registries, the presence of diabetes was defined using redeemed prescription of glucose-lowering drugs within 6 months prior to index date as was done previously.22 For co-medication, all redeemed prescriptions at any pharmacy in Denmark were identified in a 6-month lookback period from the index date. Co-medications of interest were beta-blockers, calcium channel blockers, antithrombotic drugs, diuretics, renin–angiotensin system inhibitors, nitrates, and Vaughan-Williams class I or III antiarrhythmic drugs (please see online supplemental table 1 for all ICD-10 and ATC codes used throughout the study).
Supplemental material
Statistical analysis
The time origin of the analyses was 1 June 2001 (start of the Danish Cardiac Arrest Registry). Subjects were followed until OHCA, death (not classified as an OHCA), date of emigration or 31 December 2019 (end of study), whichever came first. Conditional logistic regression models were fitted to the nested case–control data to estimate the adjusted ORs with 95% CI of OHCA comparing FQs with amoxicillin. The models were adjusted for the following prespecified well-known risk factors of OHCA: ischaemic heart disease, heart failure, atrial fibrillation, cerebrovascular disease, peripheral artery disease, diabetes mellitus, chronic obstructive pulmonary disease and chronic kidney disease. The main analyses were repeated by stratifying according to sex, age (<65 and ≥65 years of age) and history of cardiovascular disease, including heart failure and ischaemic heart disease, to investigate a potential effect modification. The presence of interaction on a multiplicative scale was estimated by including the cross-product of the two factors of interest as a variable in the model. P values of <0.05 were considered as a statistically significant difference among the groups. Descriptive baseline characteristics of the study population are presented as counts and percentages for categorical variables and as mean and SD for continuous variables.
Results
Population characteristics
The study population consisted of 46 578 cases with OHCA and 232 890 matched non-OHCA controls from the general population. Because of matching, sex and age composition was identical for OHCA cases and non-OHCA controls, with 66.8% of patients being men at a mean age of 71 years (SD 14.40). Further, the overall comorbidity burden was higher for OHCA cases than non-OHCA controls. For instance, ischaemic heart disease was prevalent in 25.91% of OHCA cases vs 10.35% of non-OHCA controls, heart failure in 20.31% of OHCA cases vs 18.39% of non-OHCA controls, and atrial fibrillation in 18.39% of OHCA cases vs 7.16% of non-OHCA controls (table 1). Likewise, use of cardiovascular drugs was more prevalent among OHCA cases than non-OHCA controls (table 1). Table 2 presents the characteristics of OHCA cases stratified by the use of FQs and amoxicillin. Users of FQs were older (76 vs 72 years) and had a significantly higher prevalence of ischaemic heart disease, diabetes mellitus and chronic kidney disease than users of amoxicillin (table 2). Furthermore, beta-blocker drug use was significantly higher for users of FQs than users of amoxicillin (table 2).
Association between FQs and OHCA compared with amoxicillin
Figure 1 shows the results related to OHCA. Within 14 days prior to index date, FQ was used by 276 OHCA cases and 328 non-OHCA controls and conferred no increase in the odds of OHCA compared with patients exposed to amoxicillin after controlling for the relevant confounders (OR 0.91 (95% CI: 0.71 to 1.16), figure 1). The majority of FQs used consisted of ciprofloxacin (cases: n=240 (0.52%), controls: n=308 (0.13%); OR 0.85 (95% CI: 0.66 to 1.10)), followed by moxifloxacin (cases: n=32 (0.07%), controls: n=16 (0.01%); OR 1.92 (95% CI: 0.96 to 3.85)). When performing stratified analyses, the OR of OHCA with FQ use did not vary significantly by sex (ORmen 0.96 (95% CI: 0.70 to 1.31), ORwomen 0.80 (95% CI: 0.53 to 1.20), p value interaction=0.9698, figure 1) and age (OR≤65 0.96 (95% CI: 0.53 to 1.74), OR>65 0.88 (95% CI: 0.67 to 1.16), p value interaction=0.7818, figure 1). Similarly, we found no significant differences in the OR of OHCA with FQ use when we performed stratified analyses by pre-existing cardiovascular disease (ORabsent 1.02 (95% CI: 0.57 to 1.82), ORpresent 0.98 (95% CI: 0.75 to 1.28), p value interaction=0.3884, table 3), including ischaemic heart disease (ORabsent 0.85 (95% CI: 0.64 to 1.12), ORpresent 1.38 (95% CI: 0.86 to 2.21), p value interaction=0.6230, table 3) and heart failure (ORabsent 0.93 (95%: 0.72–1.22), ORpresent 1.11 (95% CI: 0.61 to 2.02), p value interaction=0.7083, table 3).
Discussion
In this nationwide study including data from more than 45 000 OHCAs of presumed cardiac cause in Denmark, current FQ use was not significantly associated with increased risk of OHCA compared with amoxicillin, despite users of FQs being older and having a higher comorbidity burden than users of amoxicillin. This lack of association was consistent in men and women, in all age categories, and in the presence or absence of cardiovascular disease.
FQs are relatively commonly prescribed antibiotics due to their broad spectrum of antimicrobial activity.9 10 Although FQ use is generally well tolerated and effective, the use of these agents is problematic because of previous studies linking FQs with QT interval prolongation due to blockage of cardiac potassium channels,11 12 while certain antibiotics in this class have been withdrawn from the European and US markets entirely due to QT interval prolongation (ie, sparfloxacin, grepafloxacin).27 Prolongation of the QT interval is considered a risk marker for torsade de pointes arrhythmia.28 However, it remains questionable whether this blockage of cardiac potassium channels by FQs translates into a higher risk of OHCA in a real-world clinical setting, since previous studies that have investigated the association between use of FQs and cardiac arrhythmia/cardiac arrest obtained conflicting results.13 14 29 30 A nested case–control study by Lapi et al studied the relationship between FQ use and serious arrhythmia (defined as ventricular arrhythmia or sudden/unattended death) and reported a twofold increased risk of serious arrhythmia with FQ use.13 These findings were supported by a study by Zambon et al where the association between treatment with FQ and the risk of ventricular arrhythmia and cardiac arrest was investigated.14 That study reported a fourfold increased risk of ventricular arrhythmia and cardiac arrest associated with FQ use. In our study, comprising a nationwide cohort of patients who had an OHCA, we were not able to reproduce these findings. We consistently showed no significant association between the use of FQs and the risk of OHCA compared with amoxicillin in the general population as well as in high-risk patients such as in women (who have smaller repolarisation reserve than men due to lower expression of repolarisation channels31) or in individuals with diseases associated with potassium channel downregulation (eg, heart failure).32 These differences may be due to different designs. First, both referenced studies had limited sample size or were limited by the use of in-hospital diagnoses to detect cardiac arrest, which may result in important inclusion bias by omitting cardiac arrest victims who died prior to hospital admission. Second, confounding by indication may play an important role in both referenced studies since FQ use was compared with no use of antibiotics. Consequently, it cannot be ruled out that the reported findings were attributable to acute infections as previous studies reported wide range of mechanisms (eg, electrolyte disturbance, acute kidney failure, inflammatory disease) by which acute infection can further prolong the QT interval and predispose to cardiac arrhythmia in the presence of QT interval-prolonging drugs.23 33 Since we used an active comparator design in which the use of FQ was directly compared with the use of amoxicillin, we expect that our study would not be biased by this. Inghammar et al reported that FQ use was not associated with increased risk of serious arrhythmia.29 However, data were not based on a cohort that was specifically designed to study OHCA, and this may have caused misclassification of the outcome. A cohort study by Chou et al investigated the risk of cardiac arrhythmia among patients using moxifloxacin, levofloxacin and ciprofloxacin and reported that moxifloxacin use was associated with a 3.30-fold increased risk of ventricular arrhythmia compared with amoxicillin–clavulanate, while no increased risk of ventricular arrhythmia was observed with levofloxacin or ciprofloxacin use.30 These findings were supported by a study by Cho and Park where the association between treatment with FQ and the risk of ventricular arrhythmia was evaluated.34 The authors described that moxifloxacin increased the risk of serious ventricular arrhythmia compared with cefixime, while ciprofloxacin and levofloxacin were not associated with increased risk of serious ventricular arrhythmia.34 In our study, we did not find a statistically significant association between moxifloxacin and OHCA. It is, however, possible that a lack of statistical power masked an otherwise significant association (in our study, only 32 OHCA cases used moxifloxacin during the study period), which is highlighted by the wide CI. Further research is needed in order to replicate our findings in other settings before conclusions can be drawn regarding the safety of FQs pertaining to OHCA.
We noticed in the present study that the prevalence of risk factors that increase OHCA risk, in particular cardiovascular comorbidities, was higher among users of FQs than among users of amoxicillin. It is likely that the higher prevalence of cardiovascular comorbidities among users of FQs is driven by the higher age of FQ users (76 vs 72 years). Nonetheless, despite having a less favourable risk profile regarding OHCA risk (ie, higher age and more cardiovascular comorbidities) than users of amoxicillin, users of FQs did not have a higher OHCA risk. Furthermore, our stratified analyses according to cardiovascular comorbidities, in which we observed no significant differences in OHCA risk in those with or without the presence of cardiovascular risk comorbidities, provided additional support for the notion that it is unlikely that our results could be explained by the differences in characteristics between users of FQs and users of amoxicillin. Moreover, we have also adjusted for these variables in our multivariate model. Taking these findings together, despite previous reports in the literature of increased risk of OHCA with FQs, using a nationwide cohort of patients who had an OHCA, we were not able to reproduce this finding. Our data are noteworthy, given that FQs are relatively commonly prescribed antibiotics in the clinical practice.
Strengths and limitations
The main strength of the current study is its population-based design, allowing better generalisability to routine care. Further, the Danish Cardiac Arrest Registry allows to include large and unselected number of OHCA cases, thereby minimising the risk of inclusion bias and selection bias. Several important limitations must be acknowledged. First, the Danish registries do not hold information on potentially important confounders, such as lifestyle factors (body mass index, smoking, alcohol use), left ventricular ejection fraction and electrolyte abnormalities (eg, hypokalaemia), Consequently, despite adjustment for potential confounders, residual confounding could not be ruled out. However, considering the unexpected, and therefore unpredictable nature of OHCA, it is very hard—if not practically impossible—to obtain data on some clinical variables (such as left ventricular ejection fraction, serum potassium levels) shortly before the OHCA occurrence in a uniform manner across the study population. Hence, such information is not systematically available throughout the registries. Second, misclassification of the comorbidities could occur as not all the diagnostic codes used in the definition of covariates have been validated. However, the majority of codes used for defining important covariates used in this study have undergone scrutiny for data quality with high positive predictive values.19 35 Third, although drug dispensing records were complete, data on actual drug intake were not available throughout the registries which could result in misclassification of the exposure. However, we have no reason to assume that such misclassification would be distributed unequally among the cases and controls. In any case, drug dispensing records are already one step closer to actual intake than drug prescription records. Finally, although OHCAs from obvious non-cardiac causes (eg, trauma, drug overdose, attempted suicide) have been excluded, the possibility of misclassification of the outcome could not be excluded, because information regarding the exact cause of OHCA was not available for all the patients since autopsies were not performed for all patients who had an OHCA.
Conclusion
In this nationwide nested case–control study, we did not find evidence to support that treatment with FQs was associated with increased risk of OHCA. OHCA in patients using FQs therefore is likely the result of the underlying diseases (cardiovascular, inflammatory diseases) and not different from patients using amoxicillin. This lack of association was consistent in men and women, in all age categories, and in the presence or absence of cardiovascular disease.
Data availability statement
No data are available. The data underlying this article cannot be shared publicly due to ethical/privacy reasons.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the Danish Data Protection Agency (reference no. 2007-58-0015, local reference no. GEH-2014-017, I-Suite 0.2735). In Denmark, ethical approval is not required for observational studies where patients remain anonymous.
Acknowledgments
The authors greatly appreciate the contributions and support of all participating regional ambulance services and fire brigades.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors VE wrote the manuscript. TEE conceived the study idea, performed the analyses and wrote the manuscript. All authors critically revised and approved the manuscript. TEE is responsible for the overall content as the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.