Use of azithromycin and risk of ventricular arrhythmia

Gianluca Trifirò; Maria de Ridder; Janet Sultana; Alessandro Oteri; Peter Rijnbeek; Serena Pecchioli; Giampiero Mazzaglia; Irene Bezemer; Edeltraut Garbe; Tania Schink; Elisabetta Poluzzi; Trine Frøslev; Mariam Molokhia; Igor Diemberger; Miriam C.J.M. Sturkenboom

doi:10.1503/cmaj.160355

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Figure 1:
Selection of study cohort from 7 databases. AARHUS = Aarhus University Hospital Database, ERD = Emilia-Romagna Database, GePaRD = German Pharmacoepidemiological Research Database, HSD-CSD-LPD = Health Search Database Cegedim Strategic Data Longitudinal Patient Database, IPCI = Integrated Primary Care Information, PHARMO = PHARMO Database Network, THIN = The Health Improvement Network.
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Figure 2:
Database-specific risk of ventricular arrhythmia associated with current use of azithromycin compared with current use of amoxicillin (2-stage random-effects model). Values greater than 1.0 indicate an increased risk of ventricular arrhythmia with use of azithromycin (values plotted on logarithmic scale). Cochran Q = 0.08; p = 0.1; I² = 51%. CI = confidence interval, OR = odds ratio. *Databases with fewer than 3 exposed cases were not included in the model.
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Figure 3:
Database-specific risk of ventricular arrhythmia associated with current use of azithromycin versus nonuse of antibiotics (2-stage random-effects model). Values greater than 1.0 indicate an increased risk of ventricular arrhythmia with use of azithromycin (values plotted on logarithmic scale). Cochran Q = 3.4; p = 0.3; I² = 11.4%. CI = confidence interval, OR = odds ratio. *Databases with fewer than 3 exposed cases were not included in the model.

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Table 1:

Features of the databases included in the study

Database	Country	Type of database and setting	Study period	Diagnosis coding	Prescription coding	Source population
AARHUS	Denmark	NHS-linked regional database (northern and central regions); community, and in- and outpatient hospital settings	2000–2010	ICD-10	ATC	1 559 718
ERD	Italy	NHS-linked regional database (Emiglia-Romagna region); community setting	2005–2010	ICD-9-CM	ATC	6 079 798
HSD-CSD-LPD	Italy	Nationwide general practice database; community setting	2000–2010	ICD-9-CM and free text	ATC	1 240 561
GePaRD	Germany	Nationwide general practice database; community and hospital settings	2005–2009	ICD-10-GM	ATC	7 285 935
IPCI	Netherlands	Nationwide general practice database; community setting	1998–2010	ICPC and free text	ATC	1 016 632
PHARMO	Netherlands	Nationwide record linkage system; community setting	1999–2009	ICD-9-CM	ATC	4 625 868
THIN	United Kingdom	Nationwide general practice database; community setting	1997–2010	Read codes and free text	BNF/multilex	6 951 894

Note: AARHUS = Aarhus University Hospital Database; ATC = Anatomic Therapeutic Chemical drug classification; BNF = British National Formulary codes; ERD = Emilia-Romagna Database; GePaRD = German Pharmacoepidemiological Research Database; HSD-CSD-LPD = Health Search Database Cegedim Strategic Data Longitudinal Patient Database; ICD-9-CM = International Classification of Diseases, ninth edition, clinical modification; ICD-10 = International Classification of Diseases, 10th edition; ICD-10-GM = International Classification of Diseases, 10th edition, German modification; ICPC = International Classification of Primary Care; IPCI = Integrated Primary Care Information Database; NHS = National Health Service; THIN = The Health Improvement Network.

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Table 2:

Demographic and clinical characteristics of ventricular arrhythmia cases and matched controls in an inception cohort of new users of antibiotics across all databases (1-stage pooling)

Characteristic	Group; no. (%) of patients^*		p value
Characteristic	Cases^† n = 12 874	Controls n = 1 240 431	p value
Age, yr, mean ± SD	63.5 ± 15.3	63.6 ± 15.4	Matching factor
Age group, yr
< 60	4210 (32.7)	405 621 (32.7)
60–79	7106 (55.2)	678 516 (54.7)
≥ 80	1558 (12.1)	156 294 (12.6)
Sex			Matching factor
Male	8561 (66.5)	824 887 (66.5)
Female	4313 (33.5)	415 544 (33.5)
Well-known risk factors for ventricular arrhythmia
Atrial fibrillation/flutter	2332 (18.1)	61 844 (5.0)	< 0.001
Cardiomyopathy	1097 (8.5)	10 887 (0.9)	< 0.001
Cerebrovascular event	1539 (12.0)	81 444 (6.6)	< 0.001
Coronary artery disease	5919 (46.0)	229 811 (18.5)	< 0.001
Electrolyte imbalance	1100 (8.5)	57 663 (4.6)	< 0.001
Heart failure	2913 (22.6)	54 114 (4.4)	< 0.001
Hypertension	10 254 (79.6)	730 389 (58.9)	< 0.001
Peripheral arterial disease	626 (4.9)	26 970 (2.2)	< 0.001
Prior use of anti-arrhythmic drugs	1009 (7.8)	13 865 (1.1)	< 0.001
Concomitant use^‡ of medications known to induce hypokalemia	4661 (36.2)	211 284 (17.0)	< 0.001
Concomitant use^‡ of QT-interval–prolonging drugs^§	2089 (16.2)	75 177 (6.1)	< 0.001
Potential risk factors for ventricular arrhythmia^¶
Alcohol abuse	343 (2.7)	12 157 (1.0)	< 0.001
Chronic liver disease	683 (5.3)	43 325 (3.5)	< 0.001
Chronic respiratory disease	5310 (41.2)	390 364 (31.5)	< 0.001
Conduction disorders	1146 (8.9)	27 911 (2.3)	0.001
Congenital heart disease	151 (1.2)	2968 (0.2)	< 0.001
Diabetes mellitus	2395 (18.6)	140 208 (11.3)	< 0.001
Hyperthyroidism	300 (2.3)	16 195 (1.3)	< 0.001
Hypothyroidism	1033 (8.0)	68 233 (5.5)	< 0.001
Acute and chronic renal failure	802 (6.2)	23 324 (1.9)	< 0.001
Lipid metabolism disorders	5906 (45.9)	351 428 (28.3)	< 0.001
Obesity	1223 (9.5)	71 835 (5.8)	< 0.001
Other cardiac arrhythmias^**	1394 (10.8)	34 920 (2.8)	< 0.001
Cardiac valve disorders	1012 (7.9)	28 970 (2.3)	< 0.001

Note: SD = standard deviation.
↵* Unless stated otherwise.
↵† Current users of both azithromycin and other antibiotics were not included in the analysis.
↵‡ Within 3 mo before index date.
↵§ Use of drugs with established torsadogenic risk according to CredibleMeds list.27
↵¶ Information on smoking status was partly available only in 2 databases and therefore was not included in the final multivariate models.
↵** Except for atrial fibrillation/flutter, conduction disorders, QT-interval prolongation, ventricular arrhythmia and sudden cardiac death.

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Table 3:

Risk of ventricular arrhythmia associated with current, recent and past use of azithromycin compared with current use of amoxicillin (1-stage pooling)

Exposure^*	No. (%) of cases^† n = 479	No. (%) of controls n = 1848	OR (95% CI)
Exposure^*	No. (%) of cases^† n = 479	No. (%) of controls n = 1848	Crude^‡	Adjusted^§
Current use of amoxicillin	165 (34.4)	370 (20.0)	1.00 (ref)	1.00 (ref)
Use of azithromycin
Current	30 (6.3)	88 (4.8)	1.05 (0.63–1.74)	0.94 (0.50–1.77)
Recent	107 (22.3)	483 (26.1)	0.60 (0.44–0.83)	0.58 (0.38–0.87)
Past	177 (37.0)	907 (49.1)	0.49 (0.36–0.66)	0.52 (0.37–0.73)

Note: CI = confidence interval, OR = odds ratio, ref = reference category.
↵* Current = exposure period covered the index date (occurrence of ventricular arrhythmia) or ended within 7 days before the index date; recent = exposure period ended between 7 and 89 days before the index date; past = exposure period ended between 90 and 364 days before the index date.
↵† Current users of both azithromycin and other antibiotics were not included in the analysis.
↵‡ Crude ORs were estimated for matched case–control pairs and cannot be calculated directly from the values in this table.
↵§ Adjusted for risk factors of ventricular arrhythmia: atrial fibrillation/flutter, cardiomyopathy, coronary artery disease, cerebrovascular disorders, chronic obstructive pulmonary disease, electrolytic imbalance, heart failure, hypertension, diabetes mellitus, lipid disorder, peripheral arterial disease, hypothyroidism, prior use of antiarrhythmic drugs, concomitant use of drugs known to cause hypokalemia, and concomitant use of drugs known to prolong QT interval.

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Table 4:

Risk of ventricular arrhythmia associated with current, recent and past use of azithromycin and other antibiotics compared with nonuse of antibiotics (1-stage pooling)

Exposure^*	No. (%) of cases^† n = 12 874	No. (%) of controls n = 1 240 431	OR (95% CI)
Exposure^*	No. (%) of cases^† n = 12 874	No. (%) of controls n = 1 240 431	Crude^‡	Adjusted^§
Nonuse of antibiotics	5060 (39.3)	601 049 (48.5)	1.00 (ref)	1.00 (ref)
Use of azithromycin
Current use	30 (0.2)	1344 (0.1)	2.83 (1.97–4.08)	1.97 (1.35–2.86)
Recent use	109 (0.8)	8315 (0.7)	1.65 (1.36–2.00)	1.12 (0.92–1.37)
Past use	187 (1.5)	18 000 (1.5)	1.28 (1.10–1.48)	1.10 (0.95–1.28)
Use of other antibiotics^¶
Current use	1026 (8.0)	52 543 (4.2)	2.43 (2.27–2.60)	1.83 (1.71–1.97)
Recent use	2617 (20.3)	193 154 (15.6)	1.69 (1.61–1.77)	1.32 (1.25–1.39)
Past use	3845 (29.9)	366 026 (29.5)	1.29 (1.23–1.34)	1.11 (1.06–1.16)

Note: CI = confidence interval, OR = odds ratio, ref = reference category.
↵* Current = exposure period covered the index date (occurrence of ventricular arrhythmia) or ended within 7 days before the index date; recent = exposure period ended between 7 and 89 days before the index date; past = exposure period ended between 90 and 364 days before the index date.
↵† Current users of both azithromycin and other antibiotics were not included in the analysis.
↵‡ The crude ORs are estimated for matched case-control pairs and cannot be calculated directly from the table above.
↵§ Adjusted for risk factors of ventricular arrhythmia: atrial flutter/fibrillation, cardiomyopathy, coronary artery disease, cerebrovascular disorders, chronic obstructive pulmonary disease, electrolytic imbalance, heart failure, hypertension, diabetes mellitus, lipid disorders, peripheral arterial disease, hypothyroidism, prior use of antiarrhythmic drugs, concomitant use of drugs known to cause hypokalemia, and concomitant use of drugs known to prolong QT interval.
↵¶ Does not include amoxicillin.