It’s a drug that millions of Americans take to treat acid reflux and heartburn. Now preliminary research says proton pump inhibitors (PPIs) may increase people’s overall risk of stroke by 21 percent.

The study, which followed nearly 250,000 Danish patients for almost six years, found an association between one of the most commonly used drugs around the world and an increase in ischemic strokes.

“PPIs have been associated with unhealthy vascular function, including heart attacks, kidney disease and dementia,” said Thomas Sehested, a researcher at the Danish Heart Foundation and the study’s lead author, in a statement. “We wanted to see if PPIs also posed a risk for ischemic stroke, especially given their increasing use in the general population.”

Ischemic strokes are the most common type of stroke, accounting for up to 87 percent of all cases, according to the American Stroke Association. These strokes occur when a clot in a blood vessel cuts off blood flow to the brain.

The authors of the study presented the findings to physicians and researchers on Nov. 16 at the American Heart Association’s Scientific Sessions 2016 in New Orleans. They analyzed the records of 244,679 patients who had undergone a procedure to identify the cause of stomach issues and indigestion. During almost six years of follow-ups, nearly 9,500 suffered an ischemic stroke for the first time in their lives.

Risks Increased Significantly with Higher Doses

While the overall risk of stroke from PPIs increased by 21 percent, the risk is also dependent on the dosage. At the lowest dose, the study found there was little to no increased risk of stroke. But at higher doses, the risk increased.

Researchers broke down the stroke occurrence by each of the four PPIs: omeprazole (Prilosec), pantoprazole (Protonix), lansoprazole (Prevacid), and esomeprazole (Nexium).

At the highest dose, the stroke risk from 30 percent for lansoprazole (Prevacid) to 94 percent for pantoprazole (Protonix).

The manufacturers of the PPIs have not commented on the study because the full data has not been published for review yet, but some have continued to back their products in the media.

“Patient safety is an important priority … and we believe all of our PPI medicines are generally safe and effective when used in accordance with the label,” a spokesperson for AstraZeneca, the maker of Nexium, told CNN.

Reason for Higher Stroke Risk With PPIs Unclear

It is still unclear exactly why PPIs have a negative effect on the health of the heart. According to HealthDay, Sehested said PPIs might reduce levels of biochemicals that are important in maintaining blood vessels and keeping them from hardening.

Part of the issue facing users of PPIs is the fact that they are now sold over the counter, meaning they may be taken for longer than necessary at unregulated doses.

The authors of the study say that clinical trials and more research still needs to be done.

“One of the important takeaway messages of the study is that if you really need these medications, then you should strongly consider being on them or taking them,” said Philip Gorelick, spokesman for the American Heart Association. “However, a lot of people continue to take these medicines for prolonged periods of time, or use these medications for indications that are suspect, or not approved by the FDA.”

Using PPIs for shorter periods at lower doses may be a safer option, he continued.

Researchers in the study also looked at another group of acid-reducing medications known as H2 blockers, including Pepcid and Zantac. While they did not find a link between H2 blockers and strokes, the authors could not say whether H2 blockers would be better for patients than PPIs.

Strokes Join List of Other PPI Risks

This isn’t the first time PPIs have been linked with complications.

In 2010, the U.S. Food and Drug Administration revised its labels for over-the-counter PPIs to include a warning about an increased risk of fractures when taken at high doses. The FDA then made a safety announcement in 2011 that the drugs may cause low serum magnesium levels, which could result in muscle spasms, irregular heartbeat, and other adverse effects.

PPIs have also been linked to an increased risk of heart attacks and diarrhea when interacting with other drugs.

More recently, PPIs have come under fire for an increased risk of developing kidney disease. In April, a study published in the Journal of the American Society of Nephrology discovered that patients taking PPI had a 96 percent increased risk of kidney failure and a 28 percent increase of kidney disease when compared to those taking alternatives.

Several lawsuits have been filed against makers of PPIs for failing to warn consumers about the risk to kidneys.