Long-term Antibiotic Use Tied to Higher CVD Risk

Batya Swift Yasgur MA, LSW

May 09, 2019

Women in middle or late life who use antibiotics on a long-term basis have a higher risk for cardiovascular disease (CVD) events, new research suggests.

Investigators followed close to 36,500 female participants in the Nurses' Health Study (NSH) who were free of CVD at baseline over an 8-year period.

After adjustment for demographic, lifestyle, medical, and medication-related covariates, they found that women 60 years or older who took antibiotics for 2 months or more had the greatest risk for CVD, but long-term use of antibiotics was also associated with increased cardiovascular risk if taken by women at midlife (40–59 years).

"This new analysis from the Nurses' Health Study shows that women who take antibiotics for long periods, especially during more recent adulthood — such as in middle and late adulthood — had a higher risk of CVD in later life," senior author Lu Qi, MD, PhD, MS, director of the Tulane University Obesity Research Center, Tulane University, New Orleans, told theheart.org | Medscape Cardiology.

"The take-home message is that longer duration of antibiotic use may be linked to higher risk of CVD among women," said Qi, who is also an adjunct professor of nutrition at Harvard T.C. Chan School of Public Health, Boston.

The study was published online April 24 in the European Heart Journal.

Longitudinal Study

Several lines of research have linked antibiotic use to cardiac problems, including arrhythmias (e.g., prolongation of the QT interval, torsades de pointes, and sudden cardiac death), particular among patients with pre-existing cardiac disease, such as coronary heart disease (CHD), peripheral artery disease (PAD), infections, or pneumonia, the authors write.

However, they note, "no longitudinal study has investigated associations of duration of antibiotic use in different phases of adulthood (young, middle, and late adulthood) with the CVD incidence in a population at usual risk."

"Growing data suggest that antibiotic exposure is associated with a long-lasting alteration in gut microbiota, which have been related to CVD — the inflammation and narrowing of the blood vessels and stroke," Qi explained.

To investigate the potential association between antibiotic use and CVD, the researchers drew on data from the NHS, which contains detailed information about cumulative antibiotic use during adulthood.

The NHS is an ongoing cohort study established in 1976, consisting of 121,701 female registered nurses enrolled between 30 and 55 years and followed every 2 years.

Study data include a wide range of information on demographic, lifestyle factors, medical history, and disease status.

For the current analysis, the baseline year was set as 2004, in which information on antibiotic use was available for 90,853 women.

After excluding participants who did not meet criteria or who lacked insufficient information, the researchers included 36,469 participants in the analysis, all of whom were required to be free of CVD and cancer at enrollment.

They were grouped by age (20–39, 40–59, and 60+ years) and by duration of antibiotic use (none, <15 days, 15 days to <2 months, ≥2 months).

"Long-term" was defined as antibiotic use for at least 2 months.

The researchers calculated person-years of follow-up from the return date of the 2004 questionnaire until the date of CVD diagnosis, date of death, or end of follow-up (June 30, 2012), whichever occurred first.

There were two models used for sensitivity analysis. In the first, the covariates included reason for antibiotic use and traditional CVD risk factors (demographics, diet, lifestyle factors, and body mass index [BMI]).

Additional covariates used in model 2 included other metabolic risk factors (hypercholesterolemia, hypertension, and diabetes), as well as medication use (aspirin, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, calcium-channel blockers, statins, H2 blockers, proton pump inhibitors, and steroids).

Gut Microbiota

Women with longer duration of antibiotic use were more likely to have "unfavorable" CV risk profiles, including history of MI, higher BMI, or metabolic abnormalities such as hypertension, hypercholesterolemia, and diabetes. They were also more likely to use other medications.

Respiratory infection was the most common indication for antibiotics, with urinary tract infections and dental indications also being common.

During middle age and young adulthood, participant characteristics were similar in terms of categories of use.

During the 276,409 person-years of follow-up (average, 7.6 [SD, 1.0] years), 1056 participants developed CVD.

A longer duration of exposure to antibiotics in late- and middle-adulthood (P trend = .03 and P trend = .001, respectively) was significantly associated with higher risk for CVD in age-adjusted model.

The association remained significant in late- and middle-adulthood, even after adjusting for covariates in model 1 (P trend = .03 and P trend < .001, respectively).

In model 1, compared with women did not use antibiotics, those with long-term use in late- or middle-adulthood had an adjusted hazard ratio (HR) for CVD of 1.44 (95% CI, 1.13 - 1.85) or 1.39 (95% CI, 1.04 - 1.85), respectively.

After additional adjustment for the covariates included in model 2, long-term antibiotic use in late adulthood was significantly associated with an increased risk of CVD (HR, 1.32; 95% CI, 1.03 - 1.70).

Again, using model 2 covariates, participants with long-term use in middle adulthood were found to have a multivariate-adjusted HR of 1.28 (95% CI, 0.95 - 1.70) for CVD (P trend = .003).

By contrast, antibiotic use in young adulthood was not significantly associated with CVD incidence — results that remained similar when sensitivity analysis was performed excluding women with a history of major diseases before baseline (2004).

When outcomes of stroke and CHD were examined separately, the researchers found that women who used antibiotics for fewer than 15 days (HR, 1.56; 95% CI, 1.03 - 2.34) or 15 days to less than 2 months (HR, 1.65; 95% CI, 1.07 - 2.55) during middle adulthood showed an increased risk for CHD, compared with those who did not use antibiotics in this time period.

Risks for total exposure to antibiotics for stroke and CHD were assessed based on the sum of average days of antibiotic use after age 40.

Although there was no association found with stroke, an association was found for CHD: compared with nonusers, women who used antibiotics for an average of 15 days to less than 2 months and an average of at least 2 months had an adjusted HR of 2.30 (95% CI, 1.21 - 4.38) and 2.00 (95% CI, 1.05 - 3.79), respectively.

"Antibiotic use-induced alteration in gut microbiota may partially contribute to the increase risk of CVD," Qi commented.

"In addition, previous studies also suggest that use of antibiotics may be related to changes in lipids, inflammation, and weight gain, which may also affect cardiovascular risk," he said.

Antibiotic Stewards

Commenting on the study for theheart.org | Medscape Cardiology, Salim Hayek, MD, assistant professor, University of Michigan, Ann Arbor, who was not involved with the study, said that the findings "reinforce the notion that prolonged antibiotic [use] can be detrimental to one's health, with an emphasis on the impact of age and weight on that association."

He described the association with CHD, which was "driven by chronic inflammation," as "notable."

Hayek expressed concern that the study has several limitations, one being that the population "consisted of mostly white, highly educated women, specifically nurses, who have more intimate knowledge of healthcare, which may impact their antibiotic use."

Moreover, "antibiotic use was determined by recall, and type of antibiotics was not provided."

Last, "it is an observational study and it is impossible to account for all potential confounders of the association between antibiotic use and outcomes, and causation cannot be implied."

Nevertheless, he said, the study has important take-home messages.

"There is ample evidence that unnecessary antibiotic use is detrimental to individual and public health, including increased risks of adverse events, resistance to antibiotics, and unnecessary costs."

He emphasized that the findings "should reinforce the importance of clinicians being antibiotic stewards and avoid prescribing antibiotics except when indicated."

In a press release, Qi agreed that, indeed, the observational design cannot show conclusively that antibiotics cause CVD, only that there is an association, and that it is possible that women who reported antibiotic use "might be sicker in other ways that we were not able to measure, or there may be other factors that could affect the results that we have not been able to take account of."

Nevertheless, "our study suggests that antibiotics should be used only when they are absolutely needed" and, "considering the potentially cumulative adverse effects, the shorter time of antibiotic use, the better," he emphasized.

The study was supported by NIH grants from the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Boston Obesity Nutrition Research Center, and United States–Israel Binational Science Foundation. The authors and Hayek report no conflicting interests.

Eur Heart J. Published online April 24, 2019. Full text

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