Risk of heart valve regurgitation with fluoroquinolones

HSA would like to inform healthcare professionals about a small increased risk of heart valve regurgitation associated with the use of systemic fluoroquinolones. Fluoroquinolones are known to increase the risk of collagen-related disorders such as tendonitis, tendon rupture, and aortic aneurysm and dissection. Recently, these antibiotics have been found to be associated with regurgitation of the heart valves, another collagen-associated adverse event. 

There are seven systemic fluoroquinolones registered locally, namely ciprofloxacin, ofloxacin, norfloxacin, lomefloxacin, levofloxacin, moxifloxacin and pefloxacin. There are no inhaled fluoroquinolone-containing products registered locally.

About heart valve regurgitation¹

Heart valve regurgitation occurs when there is backflow of blood through the valve as the leaflets are closing or when there is leakage of blood through the leaflets that do not close completely. This subjects the heart to higher levels of stress and may lead to other morbidities or mortality if the condition is left untreated. Severe forms of aortic and mitral regurgitation can be life-threatening and may require surgical intervention. Causes of valvular regurgitation include degeneration, calcification, fibrosis or infection of the valve, or alteration of the valvular support structure.

Scientific literature on fluoroquinolone-induced collagen-related disorders

(a) Potential mechanisms of collagen-related disorders associated with fluoroquinolones

Fluoroquinolones have been associated with collagen-related disorders such as tendonitis, tendon rupture, and aortic aneurysm and dissection. While the mechanism behind these disorders has not been fully elucidated, in vitro studies have showed that fluoroquinolones exert various effects on different cell types, including reduced expression of extracellular matrix (ECM) proteins, upregulation of matrix metalloproteinase (MMP) expression, and inhibition of tendon cell proliferation.^2,3 It has been hypothesised that fluoroquinolone-induced collagen-related disorders may be due to increased MMP expression, resulting in damage to the collagen fibrils that are found in the Achilles tendon, aorta and heart valves.

In a recently published in vitro study, human aortic myofibroblasts were exposed to ciprofloxacin to assess the capacity for ECM dysregulation.⁴ The authors found that fluoroquinolone (ciprofloxacin) exposure resulted in decreased tissue inhibitors of matrix metalloproteinase (TIMP) expression and an increase in the MMP/TIMP ratio, as well as an attenuation of collagen-1 expression. These findings suggested that fluoroquinolone exposure induces human aortic myofibroblast-mediated ECM dysregulation through increased collagen degradation and impaired compensatory collagen deposition, which is in agreement with data from earlier studies.

(b) Disproportionality analysis and case-control study on risk of aortic and mitral regurgitation with fluoroquinolones⁵

Etminan et al. investigated the potential risk of heart valve regurgitation with fluoroquinolones, drawing from two sources of data to conduct a disproportionality analysis and case-control study.

The disproportionality analysis, which used data from the US Food and Drug Administration (FDA) adverse event reporting system (FAERS) database between 2004 and 2018, found an increased risk of valvular regurgitation with fluoroquinolone exposure (102 cases) compared to all other drugs in the database (6,099 cases), with a reported odds ratio (ROR) of 1.45 (95% CI: 1.20 – 1.77) (Table 1). Although a reduced risk was observed for moxifloxacin, the confidence interval was too wide to allow a meaningful interpretation of the data.

Table 1. Results of the disproportionality analysis of the FAERS database

Drug	Number of Cases	ROR	95% CI
Ciprofloxacin	44	1.67	1.24 – 2.25
Gatifloxacin§	6	2.87	1.29 – 6.39
Levofloxacin	52	1.80	1.37 – 2.37
Moxifloxacin	11	0.73	0.41 – 1.32
Lomefloxacin	0	-	-
Gemifloxacin§	0	-	-
Norfloxacin	0	-	-
Combined*	102	1.45	1.20 – 1.77

^§Not registered locally
*The combined number is smaller than the total number of cases as one patient could have been prescribed multiple fluoroquinolones

To further confirm the findings from their disproportionality analysis, the authors conducted a matched nested case-control study that included 12,502 cases of valvular regurgitation and 125,020 controls from a US health claims database between 2006 to 2016. The study found that current users of fluoroquinolones had a 2.4-fold and 1.75-fold increase in risk of combined aortic and mitral valve regurgitation compared to current amoxicillin and azithromycin users, respectively (Table 2). This risk remained elevated (albeit of a lower magnitude) for recent and past fluoroquinolone users. The authors added that their choice of comparator antibiotics was due to their overlapping indications (e.g. urinary tract infections and respiratory infections), which served to control for confounding by indication.

Table 2. Adjusted RRs for combined aortic and mitral valve regurgitation among fluoroquinolone users compared to amoxicillin and azithromycin users across different exposure periods^{^}

Drug	Adjusted RR (95% CI)†
	Current users	Recent users	Past users
Fluoroquinolone	2.40 (1.82 – 3.16)	1.47 (1.03 – 2.09)	1.06 (0.91 – 1.21)
Amoxicillin	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)

 

Fluoroquinolone	1.75 (1.34 – 2.29)	1.37 (0.95 – 1.98)	1.18 (1.01 – 1.38)
Azithromycin	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)

 ^{^} Current users – Active prescription up to 30 days prior to the event
   Recent users – Use within 31 to 60 days prior to the event
   Past users – Use within 61 to 365 days prior to the event

^† RRs were adjusted for variables such as sex, age, atrial fibrillation, diabetes, hypertension, coronary artery disease, stroke, chronic heart failure, chronic renal failure, and drugs that might increase the risk of valvular regurgitation, including statins, cabergoline, pergolide, and phentermine

Regulatory actions taken by overseas regulatory agencies^6,7

In September 2020, the European Medicines Agency (EMA) assessed that fluoroquinolone use may increase the risk of heart valve regurgitation. Their review considered the information from published literature, reports of fluoroquinolone-associated valvular regurgitation reported to the EU adverse events database and the assessments conducted by the pharmaceutical companies. In view of the common features in aortic aneurysm and dissection and heart valve regurgitation, the EMA recommended that the existing warnings on aortic aneurysm and dissection in the package inserts (PIs) of systemic and inhaled fluoroquinolone-containing products should be expanded to include heart valve regurgitation. A Dear Healthcare Professional Communication was also distributed in the European Union to highlight this new safety concern.

Following the European review, the UK Medicines and Healthcare products Regulatory Agency (MHRA) issued a safety update in December 2020 warning healthcare professionals of the risk of heart valve regurgitation linked to the use of systemic and inhaled fluoroquinolones. Warnings were added to the PIs for these medicines and a letter was sent to relevant healthcare professionals in the UK.

Local situation

To date, HSA has not received any local reports of heart valve-related disorders associated with fluoroquinolone use. In 2019, HSA published an article to inform healthcare professionals about an update to the local PIs of all systemic fluoroquinolones to warn about the risk of aortic aneurysm and dissection.⁸ 

HSA has reviewed the available information, taking into account the scientific literature, the biological plausibility of collagen-related disorders with fluoroquinolones, and the regulatory actions taken by EMA and UK MHRA. HSA’s assessment is that the existing warnings on aortic aneurysm and dissection should be expanded to include heart valve regurgitation as these safety issues are likely related, and is working with the pharmaceutical companies to strengthen the local PIs for all systemic fluoroquinolones to reflect this risk.

HSA’s advisory

Healthcare professionals are advised to take into consideration the above safety information when prescribing systemic fluoroquinolones and the availability of other therapeutic options for patients with pre-existing risk factors such as heart valve diseases, or predisposing conditions such as connective tissue disorders (e.g., Marfan syndrome, Ehlers-Danlos syndrome), Turner syndrome, Behçet´s disease, hypertension, rheumatoid arthritis, and infective endocarditis. Healthcare professionals are also encouraged to advise patients to seek medical attention if they experience acute dyspnoea, new onset of heart palpitations, or development of oedema, especially if they have started the fluoroquinolone therapy recently. In addition, healthcare professionals may wish to consider counselling their patients on other adverse effects associated with fluoroquinolones as appropriate, such as those involving the tendons, muscles and joints, and the nervous system.

References

1. J Am Soc Echocardiogr 2003;16:777–802
2. Toxicology 2005; 212: 24–36
3. Chang Gung Med J 2011;34:461–7
4. J Thorac Cardiovasc Surg 2019;157:109–19
5. J Am Coll Cardiol 2019;74:1444–50
6. https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-31-august-3-september-2020-prac-meeting_en.pdf
7. https://www.gov.uk/drug-safety-update/systemic-and-inhaled-fluoroquinolones-small-risk-of-heart-valve-regurgitation-consider-other-therapeutic-options-first-in-patients-at-risk
8. HSA ADR News Bulletin 2019 May; 21; 2 

Published: 12 May 2021

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