Lengthy Antibiotic Use Later in Life Tied to Higher CV Risk for Women

Antibiotic therapy that lasts for more than a few months, especially at age 60 or older, is linked to a greater risk of cardiovascular disease among women, according to a new analysis of observational data from the Nurses’ Health Study.

Earlier studies have shown mixed results as to whether antibiotics are in fact associated with cardiovascular disease, especially in those who do not yet have it. But in 2018, the US Food and Drug Administration did warn of a potentially greater risks of cardiovascular morbidity and mortality in patients with heart disease who are prescribed clarithromycin.

From the current analysis, “the most important message . . . is we should be very cautious in prescribing antibiotics” and only give them when necessary, senior author Lu Qi, MD (Tulane University, New Orleans, LA), told TCTMD. “We should also reduce the duration of antibiotic use, since the shorter the better.”

Qi credits the effect of antibiotics on the gut microbiota as the most likely mechanism. “In the past few years, there are a lot of data coming out showing that the microbiota relates to various diseases, not only cardiovascular disease but also diabetes [and] obesity,” he said, adding, “Of course, there are other potential mechanisms.”

To TCTMD, Erin Michos (Johns Hopkins University School of Medicine, Baltimore, MD), emphasized that, by design, Nurses’ Health Study analyses can only show association, not causation.

“Antibiotics are prescribed for the purpose of treating infections. Thus, longer durations of antibiotic exposure are a marker of repeated/prolonged exposures to infections and inflammation,” Michos, who was not involved in the research, commented in an email. “In my mind, it is entirely plausible that it is not the antibiotics per se causing the increased CVD risk, but the underling infections themselves.”

This study alone isn’t enough to justify changes in clinical practice, according to Michos. That said, she added, “there are many good reasons to be using antibiotics judiciously and more wisely anyway. Antibiotic resistance is a major problem and an urgent health threat. We need to be able to use these antibiotics when we really need them to treat serious bacterial infections.”

Lead author Yoriko Heianza, MD (Tulane University), Qi, and their co-investigators outline the findings in a paper published online today in the European Heart Journal.

More CHD, Stroke Seen Over Nearly 8 Years

Among the cohort of 36,429 women initially free of CVD who were surveyed about their antibiotic use in 2004 as part of the Nurses’ Health Study, Heianza et al found that 1,056 developed CVD over 276,409 person-years of follow-up (median 7.6 years). They divided the women into three groups based on their age at the time of antibiotic use: young (20 to 39 years), middle (40 to 59 years), and late (60 years and above). They then looked at the potential effects of antibiotics based on the duration of therapy: none, < 15 days, 15 days to < 2 months, and ≥ 2 months.

Women who took antibiotics for longer periods of time tended to have a family history of MI, higher body mass index, and comorbidities like hypertension, hypercholesterolemia, and diabetes. They also were more likely to be on concomitant medications. For antibiotics, the most common indications were respiratory infection, followed by urinary tract infections and dental indications.

Adjusted for demographic factors, diet and lifestyle, reasons for antibiotic use, overweight or obesity, disease status, and other medication use, late antibiotic use for more than 2 months was associated with a greater risk of developing CVD, defined as coronary heart disease or stroke (HR 1.32, 95% CI 1.03–1.70). Use in middle age showed a trend in this direction (HR 1.28; 95% CI 0.95-1.70), with increasingly higher risk at longer durations (P = 0.003). But there was no link between antibiotic use by young women and later CVD risk. Shorter durations also had no significant impact on the likelihood of CVD, regardless of age.

But Why?

As to whether there might be differences among various antibiotic types, Qi said: “Unfortunately, we don’t have detailed information regarding the different medicines in our cohort.” He stressed that it’s important to interpret the study’s findings cautiously, given its observational design and the fact that the data come from a single source, and not assume the link is causal.

If changes in the balance of gut bacteria are to blame for the added CV risk, it would stand to reason that restoring the balance through probiotics or other measures is a “potential way to minimize the risk,” he suggested.

Other potential mechanisms are that antibiotics “may induce prolongation of the QT interval and the Torsades de Pointes, and sudden cardiac death. Antibiotics can stimulate proliferation and activity of macrophages, which may induce accumulation of lipids and atherosclerosis in [the] long term,” the paper notes, suggesting that the drugs might also promote inflammation.

Exposure to antibiotics at older ages is likely a marker of individuals who are in poorer health [rather] than an acute biological process induced by the antibiotics themselves. Erin Michos

Michos sees the role of inflammation from a different angle.

“There is a large amount of emerging evidence implicating inflammation in the pathogenesis of atherothrombosis,” she explained. “Repeated infections lead to systemic inflammation and stress on the body (ie, activation of symptomatic nervous system, release of stress hormones), which in turn may be the causal triggers of increased CVD risk. Use of antibiotics may just be a good surrogate for all of this.”

Adjusted analyses can help, but they can’t remove all the potential for residual confounding, she stressed.

“The authors suggest a mechanism of antibiotics altering the gut microbiome, but what is puzzling to me is that the risk was only seen in older women,” Michos pointed out. “If alteration of gut flora were a major mechanism, why wouldn’t this affect younger and middle-aged women who would have had more decades of exposure to this altered gut microbiome?” 

Instead, “exposure to antibiotics at older ages is likely a marker of individuals who are in poorer health [rather] than an acute biological process induced by the antibiotics themselves.”

Michos concluded: “Concerns for later life increased CVD risk because of use of antibiotics are not the top of my concerns—obviously, you still need to treat individuals with serious bacterial infections with appropriate use of antibiotics. Nevertheless, this is yet another reason to avoid handing out antibiotics like candy for every little sniffle that most likely will be due to a viral [upper respiratory infection].”